Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

ABSTRACT

GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: 
                         
wherein R 1a , R 1b , R 1c , R 1d , R 2 , R 2a , and A are as defined herein, including stereoisomers, esters, solvates and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/210,470, filed Jul. 14, 2016, which is a continuation of U.S. patentapplication Ser. No. 14/592,690, filed Jan. 8, 2015, now issued as U.S.Pat. No. 9,422,310 on Aug. 23, 2016, which is a continuation of U.S.patent application Ser. No. 13/910,961 filed Jun. 5, 2013, now issued asU.S. Pat. No. 8,952,161 on Feb. 10, 2015, which is a continuation ofU.S. patent application Ser. No. 13/293,943 filed Nov. 10, 2011, nowissued as U.S. Pat. No. 8,481,738 on Jul. 9, 2013, which is a divisionalof U.S. patent application Ser. No. 12/594,809, filed Feb. 22, 2010, nowissued as U.S. Pat. No. 8,084,614 on Dec. 27, 2011, which application isa U.S. national stage application filed under 35 U.S.C. § 371 ofInternational Patent Application No. PCT/US2008/059438, accorded aninternational filing date of Apr. 4, 2008, which claims the benefit ofU.S. Provisional Application No. 60/910,621, filed Apr. 6, 2007, all ofwhich applications are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION Technical Field

This invention relates generally to gonadotropin-releasing hormone(GnRH) receptor antagonists, and to methods of treating disorders byadministration of such antagonists to a warm-blooded animal in needthereof.

Description of the Related Art

Gonadotropin-releasing hormone (GnRH), also known as luteinizinghormone-releasing hormone (LHRH), is a decapeptide(pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂) that plays an importantrole in human reproduction. GnRH is released from the hypothalamus andacts on the pituitary gland to stimulate the biosynthesis and release ofluteinizing hormone (LH) and follicle-stimulating hormone (FSH). LHreleased from the pituitary gland is responsible for the regulation ofgonadal steroid production in both males and females, while FSHregulates spermatogenesis in males and follicular development infemales.

Due to its biological importance, synthetic antagonists and agonists toGnRH have been the focus of considerable attention, particularly in thecontext of prostate cancer, breast cancer, endometriosis, uterineleiomyoma (fibroids), ovarian cancer, prostatic hyperplasia, assistedreproductive therapy, and precocious puberty (The Lancet 358:1793-1803,2001; Mol. Cell. Endo. 166:9-14, 2000). For example, peptidic GnRHagonists, such as leuprorelin(pGlu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt), have been used to treatsuch conditions. Such agonists appear to function by binding to the GnRHreceptor in the pituitary gonadotropins, thereby inducing the synthesisand release of gonadotropins. Chronic administration of GnRH agonistsdepletes gonadotropins and subsequently down-regulates the receptor,resulting in suppression of steroidal hormones after some period of time(e.g., on the order of 2-3 weeks following initiation of chronicadministration).

In contrast, GnRH antagonists are believed to suppress gonadotropinsfrom the onset, and thus have received the most attention over the pasttwo decades. To date, some of the primary obstacles to the clinical useof such antagonists have been their relatively low bioavailability andadverse side effects caused by histamine release. However, severalpeptidic antagonists with low histamine release properties have beenreported, although they still must be delivered via sustained deliveryroutes (such as subcutaneous injection or intranasal spray) due tolimited bioavailability.

In view of the limitations associated with peptidic GnRH antagonists, anumber of nonpeptidic compounds have been proposed. Recently publishedPCT applications which disclose compounds and their use as GnRHantagonists include WO 00/69859, WO 01/29044, WO 01/55119, WO 03/013528,WO 03/011870, WO 03/011841, WO 03/011839, WO 03/011293, WO 05/007164, WO05/007165 and WO 05/007633.

While significant strides have been made in this field, there remains aneed in the art for effective small molecule GnRH receptor antagonists.There is also a need for pharmaceutical compositions containing suchGnRH receptor antagonists, as well as methods relating to the usethereof to treat, for example, sex-hormone related conditions. Thepresent invention fulfills these needs, and provides other relatedadvantages.

BRIEF SUMMARY

In brief, this invention is generally directed to gonadotropin-releasinghormone (GnRH) receptor antagonists, as well as to methods for theirpreparation and use, and to pharmaceutical compositions containing thesame. More specifically, the GnRH receptor antagonists of this inventionare compounds having the following general structure (I):

including stereoisomers, esters, solvates and pharmaceuticallyacceptable salts thereof, wherein R_(1a), R_(1b), R_(1c), R_(1d), R₂,R_(2a), and A are as defined below.

The GnRH receptor antagonists of this invention may have utility over awide range of therapeutic applications, and may be used to treat avariety of sex-hormone related conditions in both men and women, as wellas a mammal in general (also referred to herein as a “subject”). Forexample, such therapeutic applications include endometriosis, uterinefibroids, polycystic ovarian disease, dysmenorrhea, dyspareunia,menorrhagia, nonmenstrual pelvic pain, pelvic tenderness, induration,general disorders of the menstrual cycle, premature ovarian failure dueto chemotherapy or early menopause, hirsutism, precocious puberty,gonadal steroid-dependent neoplasia such as cancers of the prostate,breast and ovary, gonadotroph pituitary adenomas, adenomyosis, sleepapnea, irritable bowel syndrome, premenstrual syndrome, benign prostatichypertrophy, lower urinary tract symptoms (LUTS), contraception andinfertility (e.g., assisted reproductive therapy such as in vitrofertilization). The compounds of this invention may also be useful as anadjunct to treatment of growth hormone deficiency and short stature, andfor the treatment of systemic lupus erythematosis. The compounds alsomay be useful in combination with androgens, estrogens, progesterones,antiestrogens, antiprogestogens, angiotensin-converting enzymeinhibitors, angiotensin II-receptor antagonists, renin inhibitors,bisphosphonates and other agents for the treatment and/or prevention ofdisturbances of calcium, phosphate and bone metabolism, aromataseinhibitors, analgesics such as non-steroidal anti-inflamatory drugs(NSAIDS), other COX inhibitors, and anti-NGF agents.

The methods of this invention include administering an effective amountof a GnRH receptor antagonist, preferably in the form of apharmaceutical composition, to a mammal in need thereof. Thus, in stilla further embodiment, pharmaceutical compositions are disclosedcontaining one or more GnRH receptor antagonists of this invention incombination with a pharmaceutically acceptable carrier and/or diluent.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds and/or compositions, and are eachhereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

As mentioned above, the present invention is directed generally tocompounds useful as gonadotropin-releasing hormone (GnRH) receptorantagonists. The compounds of this invention have the followingstructure (I):

and stereoisomers, esters, solvates, and pharmaceutically acceptablesalts thereof,

wherein:

A is pyridyl, phenyl, quinolinyl, naphthyridinyl, thienopyrimidinyl, or2-oxo-pyrimidinyl wherein the pyridyl, phenyl, quinolinyl,thienopyrimidinyl or 2-oxo-pyrimidinyl are substituted with 0-5 R₄;

R_(1a) is H, halogen, C₁₋₄alkyl, alkoxy or trifluoromethyl;

R_(1b) and R_(1c) are the same or different and are independently H,halogen, hydroxy, haloC₁₋₄alkyl, —C₁₋₆alkyl-(R₅)_(p),—O—C₁₋₆alkyl-(R₅)_(p), —C₁₋₆alkyl-O—C₁₋₆alkyl-(R₅)_(p),—NR₇—C₁₋₆alkyl-(R₅)_(p), or —S(O)_(m)—C₁₋₆alkyl-(R₅)_(p);

R_(1d) is Cl, F, methyl, CF₃ or cyano;

R₂ is —C₁₋₄alkyl-(R₅)_(p);

R_(2a) is phenyl substituted with 0-4 R₃, heteroaryl substituted with0-4 R₃, C₁₋₆alkyl substituted with 0-4 R₃, aryl-C₁₋₄alkyl substitutedwith 0-4 R₃, or heteroaryl-C₁₋₄alkyl substituted with 0-4 R₃;

R₃ at each occurrence is independently halogen, cyano, halo-C₁₋₄alkyl,R₅, —C₁₋₆alkyl-(R₅)_(p), —C₁₋₆alkyl-O—C₁₋₆alkyl-(R₅)_(p),—O—C₁₋₆alkyl-(R₅)_(p), —NR₇—C₁₋₆alkyl-(R₅)_(p),—S(O)_(m)—C₁₋₆alkyl-(R₅)_(p), —O—C₁₋₆alkyl-NR₇—C₁₋₆alkyl-(R₅)_(p),heterocycle-(R₅)_(p);

R₄ at each occurrence is independently halogen, C₁₋₆alkyl,haloC₁₋₄alkyl, C₁₋₆alkoxy, hydroxy, cyano, thioC₁₋₆alkyl, —C(O)NR_(T)R₈or 5 member heteroaryl;

R₅ at each occurrence is independently H, hydroxy, —OC(O)—C₁₋₆alkyl,—OC(O)O—C₁₋₆alkyl, —OC(O)—C₁₋₆alkyl-NR₇R₈, —COOR₆, —C(O)NR₇R₈,—NR₇C(O)NR₇R₈, —S(O)₂NR₉R₉, —S(O)_(m)—C₁₋₄alkyl, —NR₇R₈, C₁₋₆alkoxy,—O-heterocycle, or heterocycle wherein said heterocycle and said—O-heterocycle are substituted with 0-4 groups selected from halogen,C₁₋₆alkyl, C₁₋₄haloalkyl, hydroxy, oxo, thio, —NH₂, —S(O)₂C₁₋₄alkyl and—COOH;

R₆ at each occurrence is independently H, C₁₋₄alkyl,C₁₋₄alkyl-O—C(O)—C₁₋₆alkyl, or C₁₋₄alkyl-O—C(O)—O—C₁₋₆alkyl;

R₇ at each occurrence is independently H, C₁₋₄alkyl, hydroxy, orheterocycle where said heterocycle is substituted with 0-4 groupsselected from halogen, C₁₋₆alkyl, hydroxy, keto, —NH₂ and —COOH;

R₈ at each occurrence is independently H, C₁₋₄alkyl, haloC₁₋₄alkyl,—C(O)—C₁₋₄alkyl, —C(O)-haloC₁₋₄alkyl, —S(O)_(m)-haloC₁₋₄alkyl or—S(O)_(m)—C₁₋₄alkyl;

R₉ at each occurrence is independently H, C₁₋₄alkyl, or —C(O)C₁₋₄alkyl;

m is 0-2; and

p at each occurrence is independently 1-3.

As used herein, the above terms have the following meaning:

“Alkyl” means a straight chain or branched, noncyclic or cyclic,unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10carbon atoms. The term “C₁₋₄ alkyl” has the same meaning as alkyl butcontains from 1 to 4 carbon atoms while the term “C₁₋₆alkyl” has thesame meaning as alkyl but contains from 1 to 6 carbon atoms.Representative saturated straight chain alkyls include methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturatedbranched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl,isopentyl, and the like. Representative saturated cyclic alkyls includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH₂-cyclopropyl,—CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl, and the like; whileunsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, andthe like. Cyclic alkyls, also referred to as “homocyclic rings,” andinclude di- and poly-homocyclic rings such as decalin and adamantyl.Unsaturated alkyls contain at least one double or triple bond betweenadjacent carbon atoms (referred to as an “alkenyl” or “alkynyl”,respectively). Representative straight chain and branched alkenylsinclude ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl,1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl,2,3-dimethyl-2-butenyl, and the like; while representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1 butynyl, and the like.

“Aryl” means an aromatic carbocyclic moiety such as phenyl or naphthyl.

“Arylalkyl” means an alkyl having at least one alkyl hydrogen atomreplaced with an aryl moiety, such as —CH₂-phenyl, and the like.

“Heteroaryl” means an aromatic heterocycle ring of 5- to 10-members andhaving at least one heteroatom selected from nitrogen, oxygen andsulfur, and wherein the nitrogen and sulfur heteroatoms may beoptionally oxidized, and containing at least 1 carbon atom, includingboth mono- and bicyclic ring systems. Representative heteroaryls include(but are not limited to) furyl, benzofuranyl, thiophenyl,benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl,quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, oxadiazolyl,thiadiazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.

“Heteroarylalkyl” means an alkyl having at least one alkyl hydrogen atomreplaced with a heteroaryl moiety, such as —CH₂pyridinyl,—CH₂pyrimidinyl, and the like.

“Heterocycle” (also referred to herein as a “heterocycle ring”) means a5- to 7-membered monocyclic, or 7- to 14-membered polycyclic,heterocycle ring which is either saturated, unsaturated or aromatic, andwhich contains from 1 to 4 heteroatoms independently selected fromnitrogen, oxygen and sulfur, and wherein the nitrogen and sulfurheteroatoms may be optionally oxidized, and the nitrogen heteroatom maybe optionally quaternized, including bicyclic rings in which any of theabove heterocycles are fused to a benzene ring as well as tricyclic (andhigher) heterocyclic rings. The heterocycle may be attached via anyheteroatom or carbon atom. Heterocycles include heteroaryls as definedabove. Thus, in addition to the aromatic heteroaryls listed above,heterocycles also include (but are not limited to) morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperizinyl, piperidinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

“Haloalkyl” means an alkyl group having at least one hydrogen atomreplaced with a halogen, such as trifluoromethyl and the like.

“Halogen” means fluoro, chloro, bromo or iodo, typically fluoro orchloro.

“Hydroxy” means —OH.

“Oxo” means an oxygen double bonded to a carbon (means C═O).

“Thio” means a sulfur double bonded to a carbon (means C═S).

“Alkoxy” means an alkyl moiety attached through an oxygen bridge (i.e.,—O-alkyl) and includes groups such as methoxy and ethoxy.

“Alkylthio” means an alkyl moiety attached through a sulfur bridge(i.e., —S— alkyl) and includes groups such as methylthio and ethylthio.

In an embodiment of the present invention, R_(2a) is phenyl substitutedwith n R₃ groups as shown in structure (Ia):

In embodiments of the present invention, A of structure (I) may be2-pyridyl substituted with an R₄ group and R_(2a) is phenyl substitutedwith n R₃ groups as shown in structure (II) and 3-pyridyl substituted inthe 4 and 6 positions with R₄ and R_(2a) is phenyl substituted with n R₃groups as shown in structure (III).

In an embodiment, A of structure (I) is quinolin-2-yl which may besubstituted with two R₄ as shown in structure (IV), thienopyrimidinylsuch as thieno[2,3-d]pyrimidin-4-yl as shown in structure (V), or2-oxo-pyrimidinyl as shown in structure (VI).

In an embodiment, R_(2a) of structure (I) is substituted with R₃, whereR₃ is —O—C₁₋₄alkyl-(R₅)_(p) as shown in structure (VII). Structure(VIII) shows R_(2a) of structure (I) is phenyl, n is 1, and R₃ is—O-alkyl-(R₅)_(p) where alkyl is 3 carbons and p is 2. The two R₅ may bethe same or different. Structure (IX) shows and embodiment of structure(I) where R_(1a) and R_(1c) are H, R_(1d) is Cl, and R_(1b) is—O-alkyl-(R₅)_(p).

In an embodiment, A of structure (I) is 2-pyridyl substituted with 0-4R₄.

In an embodiment, A of structure (I) is 2-pyridyl substituted with 2 R₄groups at the 3 and 5 position.

In an embodiment, A of structure (I) is 3-pyridyl substituted with 0-4R₄.

In an embodiment, A of structure (I) is 3-pyridyl substituted with 2 R₄groups at the 4 and 6 position.

In a further embodiment, A of structure (I) is4-cyano-6-trifluoromethylpyridin-3-yl.

In an embodiment, A of structure (I) is 3-cyano-5-fluoro-quinoline-2-yl.

In an embodiment, A of structure (I) is3-cyano-5-trifluoromethyl-quinoline-2-yl.

In an embodiment, A of structure (I) is 3-cyano-[1,5]naphthyridin-2-yl.

In an embodiment, A of structure (I) is phenyl substituted with 0-4 R₄.

In an embodiment, R₄ is selected from halogen, haloalkyl, alkyl andcyano.

In an embodiment, A is substituted with 2 R₄ groups wherein each R₄ isindependently selected from halogen cyano and trifluoromethyl.

R_(1a) and R_(1c), in an embodiment, are both H.

In an embodiment, R_(1d) is Cl, F, CF₃ or methyl.

In an embodiment, R_(1d) is Cl.

In an embodiment, R_(1b) is H, hydroxy, —C₁₋₆alkyl-(R₅)_(p), or—O—C₁₋₆alkyl-(R₅)_(p).

In an embodiment, R_(1b) is H, hydroxy, or —O—C₁₋₆alkyl-(R₅)_(p) whereR₅ at each occurrence is H.

In an embodiment, R_(1b) is —O—C₁₋₆alkyl-(R₅)_(p).

In an embodiment, R_(1b) is —O—C₁₋₆alkyl-(R₅)_(p) where —C₁₋₆alkyl- is—C₂₋₄alkyl-.

In an embodiment, R_(1b) is —O—C₁₋₆alkyl-(R₅)_(p) where —C₁₋₆alkyl- is—CH₂CH₂CH₂—.

In an embodiment, R_(1b) is —O—C₁₋₆alkyl-(R₅)_(p) where R₅ is hydroxy or—COOH.

In an embodiment, R_(1b) is —O—C₁₋₆alkyl-(R₅)_(p) where R₅ is H and p is1.

In an embodiment, R₂ is —C₁₋₄alkyl-(R₅)_(p) where R₅ at each occurrenceis H.

In an embodiment, R_(2a) is phenyl substituted with 0-4 R₃, heteroarylsubstituted with 0-4 R₃, aryl-C₁₋₄alkyl substituted with 0-4 R₃, orheteroaryl-C₁₋₄alkyl substituted with 0-4 R₃.

In an embodiment, R_(2a) is phenyl substituted with 0-4 R₃ or heteroarylsubstituted with 0-4 R₃.

In an embodiment, R_(2a) is phenyl substituted with 0-4 R₃ where R₃ isselected from halogen, cyano, halo-C₁₋₄alkyl, R₅, —C₁₋₆alkyl-(R₅)_(p),—C₁₋₆alkyl-O—C₁₋₆alkyl-(R₅)_(p), —O—C₁₋₆alkyl-(R₅)_(p),—NR₇—C₁₋₆alkyl-(R₅)_(p), —S(O)_(m)—C₁₋₆alkyl-(R₅)_(p),—O—C₁₋₆alkyl-NR₇—C₁₋₆alkyl-(R₅)_(p), heterocycle-(R₅)_(p).

In an embodiment, R_(2a) is a heteroaryl substituted with 0-4 R₃, whereR₃ is selected from halogen, cyano, halo-C₁₋₄alkyl, R₅,—C₁₋₆alkyl-(R₅)_(p), —C₁₋₆alkyl-O—C₁₋₆alkyl-(R₅)_(p),—O—C₁₋₆alkyl-(R₅)_(p), —NR₇—C₁₋₆alkyl-(R₅)_(p),—S(O)_(m)—C₁₋₆alkyl-(R₅)_(p), —O—C₁₋₆alkyl-NR₇—C₁₋₆ alkyl-(R₅)_(p),heterocycle-(R₅)_(p).

In an embodiment, R_(2a) is pyridyl substituted with 0-4 R₃ where R₃ isselected from halogen, cyano, halo-C₁₋₄alkyl, R₅, —C₁₋₆alkyl-(R₅)_(p),—C₁₋₆alkyl-O—C₁₋₆alkyl-(R₅)_(p), —O—C₁₋₆alkyl-(R₅)_(p),—NR₇—C₁₋₆alkyl-(R₅)_(p), —S(O)_(m)—C₁₋₆alkyl-(R₅)_(p),—O—C₁₋₆alkyl-NR₇—C₁₋₆alkyl-(R₅)_(p), heterocycle-(R₅)_(p).

In an embodiment, R_(2a) is a benzooxazole, or benzimidazole, orbenzothiazole substituted with 0-4 R₃, where R₃ is selected fromhalogen, cyano, halo-C₁₋₄ alkyl, R₅, —C₁₋₆alkyl-(R₅)_(p),—C₁₋₆alkyl-O—C₁₋₆alkyl-(R₅)_(p), —O—C₁₋₆alkyl-(R₅)_(p),—NR₇—C₁₋₆alkyl-(R₅)_(p), —S(O)_(m)—C₁₋₆alkyl-(R₅)_(p),—O—C₁₋₆alkyl-NR₇—C₁₋₆alkyl-(R₅)_(p), heterocycle-(R₅)_(p).

In an embodiment, R₃ is halogen, cyano, halo-C₁₋₄alkyl,—O—C₁₋₆alkyl-(R₅)_(p), or heterocycle-(R₅)_(p).

In an embodiment, R₃ is halogen, cyano, —O—C₁₋₆alkyl-(R₅)_(p), orheterocycle-(R₅)_(p).

In an embodiment, R₃, at one occurrence, is —O—C₁₋₆alkyl-(R₅)_(p), whereR₅ is H, hydroxy, —COOH or heterocycle where said heterocycle issubstituted with 0-4 groups selected from halogen, C₁₋₄alkyl,C₁₋₄haloalkyl, hydroxy, oxo, thio, —NH₂, —S(O)₂C₁₋₄alkyl and —COOH.

In an embodiment, R₃, at one occurrence, is —O—C₁₋₆alkyl-(R₅)_(p), whereR₅ is OH or —COOH.

In an embodiment, R₃, at one occurrence is —O—C₁₋₆alkyl-(R₅)_(p) where—C₁₋₆alkyl- is —C₂₋₃alkyl-.

In an embodiment, R₃, at one occurrence is —O—C₁₋₆alkyl-(R₅)_(p) where—C₁₋₆alkyl- is —CH₂CH₂—.

In an embodiment, one of R_(1b) and R₃ is —O—C₁₋₆alkyl-(R₅)_(p), whereR₅ is OH, —COOR₆ or heterocycle wherein said heterocycle is substitutedwith 0-4 groups selected from halogen, C₁₋₄alkyl, C₁₋₄haloalkyl,hydroxy, oxo, thio, —NH₂, —S(O)₂C₁₋₄alkyl and —COOH.

In an embodiment, one of R_(1b) and R₃ is —O—C₁₋₆alkyl-(R₅)_(p), whereR₅ is OH or —COOH.

In an embodiment, R_(1b) is —O—C₁₋₆alkyl-(R₅)_(p), where R₅ is OH or—COOH; and R_(2a) is phenyl substituted with 1-4 R₃, where R₃ isselected from halogen, cyano, CF₃, methoxy, methyl, or CO₂R.

In an embodiment, R_(1b) is hydrogen and R_(2a) is phenyl substitutedwith 1-2 R₃, where one R₃ is selected from O—C₁₋₆alkyl-(R₅)_(p) andanother R₃ is selected from hydrogen, halogen, cyano, CF₃, methoxy, ormethyl.

In an embodiment, R_(1b) is —O—CH₃ and R_(2a) is phenyl substituted with1-2 R₃, where one R₃ is selected from O—C₁₋₆alkyl-(R₅)_(p) and anotherR₃ is selected from hydrogen, halogen, cyano, CF₃, methoxy, or methyl.

In an embodiment, R₅ is heterocycle and may be:

Representative compounds of the present invention include:

-   4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methanesulfonyl-phenyl)-N-methyl-benzamide;-   4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-hydroxy-6-methyl-phenyl)-N-methyl-benzamide;-   4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-[2-(2-hydroxy-ethoxy)-6-methyl-phenyl]-N-methyl-benzamide;-   4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-[2-(2-methoxy-ethoxy)-6-methyl-phenyl]-N-methyl-benzamide;-   4-(2-{[4-Chloro-3-(3-cyano-6-fluoro-quinolin-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyric    acid;-   Acetic acid    2-(2-{[4-chlor-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-ethyl    ester,-   3-(5-Chloro-2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-propionic    acid;-   4-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methoxy-phenyl)-butyric    acid methyl ester;-   4-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methoxy-phenyl)-butyric    acid;-   4-(2-{[4-Chloro-3-(4-methyl-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methoxy-phenyl)-butyric    acid;-   4-Chloro-2-(3-dimethylamino-propoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-5-(4-methyl-6-trifluoromethyl-pyridin-3-yl)-benzamide;-   4-[5-Chloro-2-[(2-methoxy-6-methyl-phenyl)-methyl-carbamoyl]-4-(4-methyl-6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyric    acid ethyl ester;-   4-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyric    acid;-   3-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-propionic    acid;-   {5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-acetic    acid;-   4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-hydroxy-butoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide;-   4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(3-hydroxy-propoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide;-   4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2-hydroxy-ethoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide;-   4-chlor-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(3-hydroxy-propyl)-N-(2-methoxy-phenyl)-N-methyl-benzamide;-   4-chloro(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(3-hydroxy-propyl)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide;-   3-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-propionic    acid;-   3-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-6-methyl-phenyl)-methyl-carbamoyl]-phenyl}-propionic    acid;-   4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2-hydroxy-ethylsulfanyl)-N-(2-methoxy-phenyl)-N-methyl-benzamide;-   4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2-hydroxy-ethylsulfanyl)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide;-   {5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenylsulfanyl}-acetic    acid;-   {5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-6-methyl-phenyl)-methyl-carbamoyl]-phenylsulfanyl}-acetic    acid;-   4-chloro-5-(4,6-dicyano-pyridin-3-yl)-2-(2-hydroxy-ethoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide-   4-chloro-5-(4,6-dicyano-pyridin-3-yl)-2-(2-hydroxy-ethoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide;-   4-chloro-5-(4,6-dicyano-pyridin-3-yl)-2-(3-hydroxy-propoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide;-   4-chloro-5-(4,6-dicyano-pyridin-3-yl)-2-(3-hydroxy-propoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide;-   4-{5-chloro(4,6-dicyano-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyric    acid;-   4-{5-chloro-4-(4,6-dicyano-pyridin-3-yl)-2-[(2-methoxy-6-methyl-phenyl)-methyl-carbamoyl]-phenoxy}-butyric    acid;-   [5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-4-(4-prop-1-ynyl-6-trifluoromethyl-pyridin-3-yl)-phenoxy]-acetic    acid;-   3-[5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-4-(4-prop-1-ynyl-6-trifluoromethyl-pyridin-3-yl)-phenoxy]-propionic    acid;-   4-[5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-4-(4-prop-1-ynyl-6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyric    acid;-   3-(2-{[4-chloro-3-(4-prop-1-ynyl-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic    acid;-   4-(2-{[4-chloro-3-(4-ethynyl-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-butyric    acid;-   4-(2-{[4-chloro-3-(4-prop-1-ynyl-6-trifluoromethyl-pyridin-3-yl)-benzo    yl]-methyl-amino}-phenoxy)-butyric acid;-   4-(2-{[4-chloro-3-(4-ethynyl-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-butyric    acid;-   3-(2-{[4-Chloro(4,6-dicyano-pyridin-3-yl)-benzoyl]-methy-amino}-phenoxy)-propionic    acid:-   3-(2-{[4-Chloro-3-(4-ethynyl-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic    acid;-   3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenylamino)-propionic    acid;-   4-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methy-amino}-phenylamino)-butyric    acid;-   3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methy-amino}-phenoxy)-propionic    acid 1-isopropoxycarbonyloxy-ethyl ester;-   3-(2-{[4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoyl]-methyl-amino}-phenoxy)-propionic    acid;-   3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-fluoro-phenoxy)-propionic    acid;-   3-(2-{[4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoyl]-methyl-amino}-3-fluoro-phenoxy)-propionic    acid;-   3-(3-Chloro-2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic    acid;-   3-(3-Chloro-2-{[4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoyl]-methyl-amino}-phenoxy)-propionic    acid;-   3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-cyano-phenoxy)-propionic    acid;-   3-(2-{[4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoyl]-methyl-amino}-3-cyano-phenoxy)-propionic    acid;-   4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-{2-fluoro-6-[2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethoxy]-phenyl}-N-methyl-benzamide;-   4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-{2-fluoro-6-[2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethoxy]-phenyl}-2-methoxy-N-methyl-benzamide;-   4-Chloro-N-{2-chloro-6-[2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethoxy]-phenyl}-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-benzamide;-   4-Chloro-N-{2-chloro-6-[2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethoxy]-phenyl}-5-(4-cyano-6-trifluoromethyl-pyrindin-3-yl)-2-methoxy-N-methyl-benzamide;-   4-Chloro-N-{2-cyano-6-[2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethoxy]-phenyl}-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-benzamide;-   4-Chloro-N-{2-cyano-6-[2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethoxy]-phenyl}-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-methyl-benzamide;-   4-Chloro-N-{2-chloro-6-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-benzamide;-   4-Chloro-N-{2-chloro-6-[2-(l    H-tetrazol-5-yl)-ethoxy]-phenyl}-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-methyl-benzamide;-   4-Chloro-N-{2-cyano-6-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-benzamide;-   4-Chloro-N-{2-cyano-6-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-methyl-benzamide;-   4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-{2-fluoro-6-[2-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-ethoxy]-phenyl}-N-methyl-benzamide;-   4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-{2-fluoro-6-[2-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-ethoxy]-phenyl}-2-methoxy-N-methyl-benzamide;-   4-Chloro-N-{2-chloro-6-[2-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-ethoxy]-phenyl}-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-benzamide;-   4-Chloro-N-{2-chloro-6-[2-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-ethoxy]-phenyl}-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-methyl-benzamide;-   4-Chloro-N-{2-cyano-6-[2-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-ethoxy]-phenyl}-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-benzamide;-   4-Chloro-N-{2-cyano-6-[2-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-ethoxy]-phenyl}-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-methyl-benzamide;-   4-[5-Chloro-2-[(2-chloro-6-methoxy-phenyl)-methyl-carbamoyl]-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyric    acid;-   4-[5-Chloro-2-[(2-cyano-6-methoxy-phenyl)-methyl-carbamoyl]-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyric    acid;-   4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-fluoro-6-methoxy-phenyl)-N-methyl-2-[3-(1H-tetrazol-5-yl)-propoxy]-benzamide;-   4-Chloro-N-(2-chloro-6-methoxy-phenyl)-5-(4-cyano-6-trifluoromethyl-pyrindin-3-yl)-N-methyl-2-[3-(1H-tetrazol-5-yl)-propoxy]-benzamide;-   4-{5-Chloro-4-(3-cyano-5-trifluoromethyl-quinolin-2-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyric    acid;-   4-{5-Chloro-4-(3-cyano-5-trifluoromethyl-quinolin-2-yl)-2-[(2-fluoro-6-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyric    acid;-   4-[5-Chloro-2-[(2-chloro-6-methoxy-phenyl)-methyl-carbamoyl]-4-(3-cyano-5-trifluoromethyl-quinolin-2-yl)-phenoxy]-butyric    acid;-   3-(2-{[4-Chloro-5-(3-cyano-5-trifluoromethyl-quinolin-2-yl)-2-methoxy-benzoyl]-methyl-amino}-3-fluoro-phenoxy)-propionic    acid;-   3-(3-Chloro-2-{[4-chloro-5-(3-cyano-5-trifluoromethyl-quinolin-2-yl)-2-methoxy-benzoyl]-methyl-amino}-phenoxy)-propionic    acid;-   3-(2-{[4-Chloro-5-(3-cyano-5-trifluoromethyl-quinolin-2-yl)-2-methoxy-benzoyl]-methyl-amino}-phenoxy)-propionic    acid;-   3-(2-{[4-Chloro-3-(3-cyano-5-trifluoromethyl-quinolin-2-yl)-benzoyl]-methyl-amino}-phenoxy)    propionic acid;-   2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-fluoro-benzoic    acid methyl ester,-   2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-fluoro-benzoic    acid ethyl ester;-   3-Chloro-2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-benzoic    acid methyl ester,-   3-Chloro-2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-benzoic    acid ethyl ester;-   3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-2-hydroxy-propionic    acid;-   2-Amino-3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic    acid;-   (7-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-benzooxazol-2-yl)-acetic    acid;-   (7-{[4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoyl]-methyl-amino}-benzooxazol-2-yl)-acetic    acid;-   3-(7-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-benzooxazol-2-yl)-propionic    acid;-   3-(7-{[4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoyl]-methyl-amino}-benzooxazol-2-yl)-propionic    acid;-   3-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-2-hydroxy-propionic    acid;-   2-Amino-3-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-propionic    acid; and-   4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-3-hydroxy-butyric    acid.

The representative compound list above also is meant to includepharmaceutically acceptable salts of the compounds listed.

The compounds of the present invention may be prepared by known organicsynthesis techniques, including the methods described in more detail inthe Examples. In general, the compounds of structure (I) above may bemade by the following reaction schemes, wherein all substituents are asdefined above unless indicated otherwise.

A 3-bromobenzoic acid (I) is converted into the corresponding acylchloride, then is coupled with HN(R₂)R_(2a)(II) to form the amide (III).Alternatively, (III) can be prepared by a coupling reaction of (I) with(II) in presence of an activating reagent such as HBTU. Where R₂ of (II)is a hydrogen, the additional N-alkylation step may be carried out inDMF with strong base such as sodium hydride and R₂X (X═Br, I). (III) wasthen transformed into the boronic ester (IV) through a palladium (0)catalyzed reaction. Suzuki reaction of (IV) with a suitable aryl orheteroaryl halide (A-X) produces the desired product (V). Examples ofsuitable aryl or heteroaryl groups are described for A in Scheme 1.

Additionally compounds of the present invention are prepared from amodification of chemistry described in Scheme 1. According to Scheme 2,amide (III) where one of the R₃ is methoxy may be prepared according toscheme 1. De-alkylation of the methoxyphenyl group generates phenol(VI). Alkylation by substituted bromoalkanes (Br-alkyl-R₅), includingfor example bromo-alkyl esters (Br(CH₂)_(n)CO₂R₆) gives substitutedethers (VII). This intermediate is in turn converted to the boronicester (VIII) through a palladium (0) catalyzed reaction. SubsequentSuzuki reaction of (VIII) with a suitable aryl or heteroaryl halideproduces (IX). Alternatively, an appropriate aryl or hetaryl boronicacid may be coupled with (VII) under Suzuki conditions to yield (IX).

In the case where the substituent R₅ is represented by a carboxylic acidester (X), deprotection of the ester using acid or base conditions isused to produce the free carboxylic acid (XI) as depicted in Scheme 3.Compounds of general formula (X) may conversely be prepared byesterification of acids (XI) as required.

Alternatively, compounds of the general formula (IX) may also beprepared from the phenol (VI). As is shown in Scheme 4, the palladium(0) reaction is first conducted to generate the boron ester (XII). Thisintermediate is in turn subjected to Suzuki conditions with various arylbromides to yield the phenols (XIII). Subsequently alkylation of thephenolic group provides compounds of the general structure (IX).

An alternative synthesis of compounds of formula (IX) is described inScheme 5. In this case, phenol (XIII) is alkylated with 3-bromopropanolto give (XIV). Oxidation of the alcohol yields the carboxylic acid (XV).

Alternatively, (VI) may be obtained by reaction of the acyl chloride,generated in situ from the acid (I), with a N-substituted hydroxyanilineas is described in Scheme 6. Intermediate (VI) is alkylated by thecorresponding substituted alkyl bromide such as bromo-alkyl ester(Br-alkyl-COOR₀) to yield the ether (VII), which may be furtherelaborated to compounds of formula (IX) as previously described inScheme 2. In Scheme 6, the amide (VI) may either be prepared asdescribed or synthesized from a suitably substituted 2-aminocresol(R₂═H). Alkylation of the amide nitrogen may be performed at a laterstage in the reaction sequence. Typically for the case where the R₂group is a hydrogen, the additional N-alkylation step is carried out inDMF with strong base such as sodium hydride and R₂X (X═Br, I) on theintermediate (VII) before completing the additional steps in thereaction sequence.

Intermediate phenol (VI) is alkylated with 3-bromopropanol. Theintermediate bromide (XVI) is converted to the corresponding boronicester (XVII). Suzuki reaction with suitable aryl or heteroaryl halidegives the alcohol (XVIIa). This derivative may be subsequently oxidizedto yield the acid (XVIII). Optionally the acid may be converted to itsalkyl ester (XIX) directly from the acid.

In a further elaboration of Scheme 3, esters (where R₆ is, for instance,methyl or ethyl) may be subjected to aminolysis to give the amide XX.

α-Tetralone (XXI) is converted into the corresponding lactam (XXII) andthen opened to form the aniline methyl ester (XXIII). This aniline wascoupled to benzoyl chloride formed from the acid (I, see also Scheme 1)to generate the amide (XXIV, R₂═H). A subsequent N-alkylation step iscarried out in DMF with strong base such as sodium hydride and R₂X(X═Br, I) to give the fully substituted (XXIV, R₂=alkyl, R₆=methyl).Bromide (XXIV) is then transformed into the boronic ester (XXV) througha palladium (0) catalyzed reaction. Suzuki reaction with a suitable arylor heteroaryl halide yields the ester (XXVI). The ester may be convertedto the acid (XXVII) as necessary. In cases where the “A” groupintroduced is sensitive to the deprotection conditions necessary toremove the methyl ester, the ester substitution R₆ may be changed whenrequired. In this respect, ester (XXIV) is first deprotected underconditions of basic hydrolysis before re-esterification with a suitablealcohol (exemplified by R₆=tert-butyl). The final steps in Scheme 9remain constant for both intermediates.

In a variation of scheme 1, alkylation of the amide nitrogen may bedelayed to facilitate diversification of the substitution at thisposition. Thus, as is described in Scheme 10, amide (III) may beconverted first to the boron ester (XXVIII) and then to the intermediate(XIV) via the Suzuki protocol. Alkylation of the amide nitrogen iseffected by reaction with a suitable electrophilic reagent in thepresence of strong base to yield the fully substituted product (V).

In a modification of Scheme 1, the palladium coupling reactions may beperformed earlier in the reaction sequence. Thus, benzoic acid (I) isfirst transformed to its carboxylic ester and then converted to theboron ester (XXX). This intermediate is subjected to Suzuki couplingconditions resulting in compound (XXXI) after ester hydrolysis.Alternatively, commercially available (XXX.a) maybe used to produce XXXIin one step via Suzuki coupling reaction. The acid (XXXI) is activatedas the acid chloride in situ and coupled with anilines of generalstructure (II) to obtain the amides (V). When R₂ is hydrogen, asubsequent N-alkylation step may be carried out in DMF with strong basesuch as sodium hydride and R₂X (X═Br, I) to give (V).

Synthesis of appropriately substituted aniline (II) may be directlyaccomplished by reductive amination of the primary aniline (XXXII) witha carbonyl equivalent such as aldehyde, ketone or substituted ketal, orvia a 2-step route involving direct acylation. In this case, theintermediate (XXXIII, R is H, alkyl or substituted alkyl) is reducedwith, for instance, lithium aluminum hydride to generate the desiredproduct.

4-Substituted-2-fluoro 3-nitro-benzoic acid (XLI) is converted into thecorresponding acyl chloride and is coupled with a substituted aniline(II) to form the amide (XLII). Alternatively, (XLII) can be prepared bya coupling reaction of (XLI) with (II) in the presence of an activatingreagent such as HBTU. When the R₂ group of (II) is hydrogen, anadditional N-alkylation using an alkyl halide [R₂X (X═Br, I)] is carriedout under conditions such as in DMF with a strong base such as sodiumhydride. (XLII) is then transformed into the bromide (XLIII) by initialreduction of the nitro function followed by a diazotization of theaniline in the presence of copper (II) bromide. (XLV) may be prepared inseveral ways including substituting the fluoro group of (XLIII) by usingan appropriately substituted alcohol directly to insert the alkyl sidechain. Alternatively, the substitution is performed with sodiummethoxide to generate the methoxy derivative. De-methylation of thismethoxy compound is generally accomplished with BBr₃ to facilitatepreparation of the phenol which may be subsequent alkylated with asubstituted alkyl bromide (exemplified by Br-alkyl-R₅) to yield theintermediate (XLV). Bromide (XLV) may be used in a palladium (0)catalyzed reaction to give the boron ester (XLVI). Under Suzukiconditions this ester could be reacted with a suitable aryl orheteroaryl halide to yield (XLVII). Compounds of general structure(XLVII, R₅ is —COOR₆) may be converted to the (XLVIII) by deprotectionof the ester under acidic or basic conditions. Alternately, oxidation ofthe corresponding alcohol (XLVII, R₅ is hydroxy) may also yieldstructure (XLVIII). In all cases, as required, the acid could bere-converted to a suitable ester as previously described.

When A is a substituted pyridine, several additional synthetictransformations are possible and some are shown here. The substitutedpyridine (XLIX) is for example oxidized to yield an N-oxide (L) as theproduct. Additionally, when the pyridine ring contains one or morehalogens such as chlorine in an activated position (ortho or para to thepyridine nitrogen), the halogen in (LI) may be displaced by a suitablenucleophile to yield the product (LII). Such nucleophiles arerepresented by mercaptans or nucleophilic heterocycles such as pyrazoleor imidazole. Other substitution patterns within the pyridine may alsobe modified according to known general procedures for the modificationof functional groups attached to heteroaryl or aryl rings. This isexemplified in the described hydrolysis of the nitrile (LIII) wherebytreatment of compounds of this general structure with aqueous baseprovided access to the amides of general structure (LIV).

Intermediate phenol (VI) is alkylated under basic conditions to generatethe alkyl nitrile (LV). This intermediate is coupled with an activatedazide to allow for the synthesis of the tetrazole (LVI). At this stagethe tetrazole moiety is protected by reaction with a suitablesubstituted alkyl halide (such as trimethylsilylethoxy methyl chloride)possibly resulting in a mix of isomers. The resultant alkyl tetrazole(LVII) is then converted to the boron ester (LVIII) as describedpreviously before reaction with a suitable aryl or heteroaryl halideyields the protected intermediate (LIX). Subsequent deprotection of thisspecies afforded the tetrazole (LX).

Aminobenzoic acid (LXI) is condensed with urea in acetic acid at hightemperature. The resulting urea (LXII) is subjected to a secondcondensation with a suitably substituted 1,3-diketone in the presence ofa strong acid to afford the aryl ester (LXIII). Removal of the esterfunction is accomplished through acidic hydrolysis to give the acid(LXIV) which was subsequently coupled to suitably substituted anilines(II) to yield the amides (LXV).

As a variation from Scheme 13, the bromide XLIII is converted to theboronic ester (LXVI) first, then followed by Suzuki coupling to produceLXVII. The fluoride on LXVII is then replaced with an alcohol(R₅-alkyl-OH) to give the final compound LXVIII. The R₅ group may beprotected during the replacement reaction, thus a deprotection may benecessary before the final structure of LXVIII is generated.

Alternatively, the commercially available LXIX can be selectivelyalkylated to the phenol and acid groups to form LXX. After removal ofthe protectin group (prot), the amide can be formed to produce LXXI.During this process, the functional group on R₅ may be protected, thus adeprotection may be necessary.

As a variation on Scheme 11, the aminophenol LXXIII reacts withacrylonitrile to form LXXIV which can be transformed into the tetrazoleintermediate LXXV. Subsequently XXXI is activated by converting it intothe corresponding acyl chloride which then reacts with LXXV in anaqueous solution to produce the desired product LXXVI.

5-Bromo-4-R_(1d)-2-hydroxy-benzoic acid is coupled with a substitutedaniline (II) to form the amide (LXXVII) in the presence of P₂O₅.Alternatively, (LXXVII) may be prepared by a coupling reaction with (II)in the presence of an activating reagent such as HBTU. Amide (LXXVII)may be used in a palladium (0) catalyzed reaction to give the boronester (LXXVIII). Under Suzuki conditions this boronic ester could bereacted with a suitable aryl or heteroaryl halide to yield (LXXIX),which may be converted to the (LXXX) by alkylation with alkyl halides ormesylates or by a Mitsunobu reaction with alkyl alcohols.

The compounds of the present invention may generally be utilized as thefree acid or free base. Alternatively, the compounds of this inventionmay be used in the form of acid or base addition salts. Acid additionsalts of the free amino compounds of the present invention may beprepared by methods well known in the art, and may be formed fromorganic and inorganic acids which form non-toxic salts. Suitable organicacids include maleic, fumaric, benzoic, ascorbic, succinic,methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric,salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic,stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids.Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric,phosphoric, and nitric acids. Base addition salts included those saltsthat form with the carboxylate anion and include salts formed withorganic and inorganic cations such as those chosen from the alkali andalkaline earth metals (for example, lithium, sodium, potassium,magnesium, barium and calcium), as well as the ammonium ion andsubstituted derivatives thereof (for example, dibenzylammonium,benzylammonium, 2-hydroxyethylammonium, and the like). Thus, the term“pharmaceutically acceptable salt” of structure (I) is intended toencompass any and all acceptable salt forms.

In addition, prodrugs are also included within the context of thisinvention. Prodrugs are any covalently bonded carriers that release acompound of structure (I) in vivo when such prodrug is administered to apatient. Prodrugs are generally prepared by modifying functional groupsin a way such that the modification is cleaved, either by routinemanipulation or in vivo, yielding the parent compound. Prodrugs include,for example, compounds of this invention wherein hydroxy, amine or acidgroups are bonded to any group that, when administered to a patient,cleaves to form the hydroxy, amine or acid groups. Thus, representativeexamples of prodrugs include (but are not limited to) acetate, formateand benzoate derivatives of alcohol and amine functional groups of thecompounds of structure (I). Further, in the case of a carboxylic acid(—COOH), esters may be employed, such as methyl esters, ethyl esters,and the like.

With regard to stereoisomers, the compounds of structure (I) may havechiral centers and may occur as racemates, racemic mixtures and asindividual enantiomers or diastereomers. All such isomeric forms areincluded within the present invention, including mixtures thereof.

The compounds of the present invention may exist in a continum of solidstates ranging from fully amorphous to fully crystalline. Furthermore,some of the crystalline forms of the compounds of structure (I) mayexist as polymorphs, which are included in the present invention. Inaddition, some of the compounds of structure (I) may also form solvateswith water or other organic solvents. The term solvate is used herein todescribe a molecular complex comprising a compound of the presentinvention and one or more pharmaceutically acceptable solvent molecules.Such solvates are similarly included within the scope of this invention.

The present invention also includes all pharmaceutically acceptableisotopically labeled compounds of structure (I) where on or more atomsare replaced by atoms having the same atomic number but a differentatomic mass. Examples include ²H and ³H for hydrogen, ¹¹C, ¹³C and ¹⁴Cfor carbon, ³⁵Cl for chlorine, ¹⁸F for fluorine, ¹²³I and ¹²⁵I foriodine, ¹³N and ¹⁵N for nitrogen, and ³⁵S for sulfur.

Compounds of the present invention include compounds of structure (I) asdefined, including all polymorphs, prodrugs, isomers (including optical,geometric and tautomeric), salts, solvates and isotopes thereof.

The effectiveness of a compound as a GnRH receptor antagonist may bedetermined by various assay techniques. Assay techniques well known inthe field include the use of cultured pituitary cells for measuring GnRHactivity (Vale et al., Endocrinology 91:562-572, 1972) and themeasurement of radioligand binding to rat pituitary membranes (Perrin etal., Mol. Pharmacol. 23:44-51, 1983) or to membranes from cellsexpressing cloned receptors as described below. Other assay techniquesinclude (but are not limited to) measurement of the effects of GnRHreceptor antagonists on the inhibition of GnRH-stimulated calcium flux,modulation of phosphoinositol hydrolysis, activation of ERK1/2, mastcell histamine release, and the circulating concentrations ofgonadotropins in the castrate animal. Descriptions of these techniques,the synthesis of radiolabeled ligand, the employment of radiolabeledligand in radioimmunoassay, and the measurement of the effectiveness ofa compound as a GnRH receptor antagonist follow.

Cloning and Expression of GnRH Receptors

cDNA's of human, rhesus macaque, rabbit, dog and rat GnRH receptors arecloned into pcDNA3.1 (+) (Invitrogen). Full length sequences of allreceptors are confirmed by DNA sequencing. HEK 293, CHO, COS-7, or ratbasophilic leukemia (RBL) cells are stably transfected with human, rat,or macaque GnRH receptors and high expressing single cell clones(B_(max)≥0.4 pMol/mg membrane protein) are isolated and maintained inDulbecco's Modified Eagles Medium (DMEM) with following supplements: 10mM HEPES; 2 mM L-glutamine; 1 mM Sodium Pyruvate; 50 U/mL penicillin, 50μg/mL streptomycin; 10% Heat-inactivated Fetal Bovine Serum and 200μg/mL Geneticin (G-418-Sulfate). Non-essential amino acids (0.1 mM)(Irvine Scientific; Santa Ana, Calif.) are included in the RBL cellmedia.

In general, initial peptide radioligand binding assays are carried outusing membranes from stably transfected RBL cells. RBL stable clones arefound to more consistently express high levels of GnRH receptor and aretherefore used for subsequent binding studies as well as Ca⁺⁺ flux andinositol phosphate accumulation assays. Transiently transfected COS-7cells are used for preparation of membranes containing GnRH receptorsfrom multiple species (as well as those of mutant receptors for otherstudies) because of the convenience for rapidly analyzing multiplereceptors. Stably transfected CHO cells are used for ERK1/2 stimulationassays because of superior signal/noise characteristics in this assay.

Membrane Preparation

HEK293 cells stably transfected with the human GnRH receptor are grownfor two days after achieving confluence then are harvested by strikingtissue culture flasks against a firm surface. Cells are collected bycentrifugation at 1000 g for 5 minutes. Cell pellets are resuspended in5% sucrose and homogenized using a polytron homogenizer for two 15second homogenization steps. Cell homogenates are then centrifuged for 5minutes at 3000 g to remove nuclei and the supernatant subsequentlycentrifuged for 30 minutes at 44,000 g to collect the membrane fraction.The membrane pellet is resuspended in GnRH binding buffer (10 mM HEPES,pH 7.5, 150 mM NaCl and 0.1% BSA) and aliquots immediately snap-frozenin liquid nitrogen and stored at −80° C. Protein content of the membranesuspension is determined using the Bio-Rad protein assay kit (Bio-Rad).

RBL cells stably transfected with the human GnRH receptor are grown to80% confluency prior to harvesting. The cells are incubated at 37° C.for 10 min in 0.5 mM EDTA/PBS (Ca⁺⁺, Mg⁺⁺ free), and are dislodged fromthe plate by gentle rapping of the flasks. Cells are collected andpelleted by centrifugation at 1000 g for 5 minutes. Cell pellets areresuspended in buffer (DPBS supplemented with 10 mM MgCl₂, 2 mM EGTA,pH=7.4), and cell lysis is performed using a pressure cell and applyingN₂ at a pressure of 900 psi for 30 min at 4° C. Unbroken cells andlarger debris were removed by centrifugation at 1200 g for 10 min at 4°C. The cell membrane supernatant is then centrifuged at 45,000 g and theresulting membrane pellet is resuspended in assay buffer and homogenizedon ice using a tissue homogenizer. Protein concentrations are determinedusing the Coomassie Plus Protein Reagent kit. Membranes are aliquotedand stored at −80° C. until ready for use.

COS-7 cells transiently transfected with GnRH receptors from differentspecies (human, macaque, dog, rabbit, rat) or mutant GnRH receptors areprepared by bulk electroporation. COS-7 cells are obtained from AmericanType Cell Culture (Manassas, Va.) and are maintained in Dulbeccos'smodified Eagle's medium (DMEM) (MediaTech Inc., Herndon, Va.) containing10% fetal bovine serum, 10 mM HEPES, 2 mM L-glutamine, 1 mM sodiumpyruvate, 50 U/mL penicillin, 50 μg/mL streptomycin. COS-7 cells areseeded in 500 cm² tissue culture plates and grown to confluency prior tocell transfection. 5×10⁷ cells are transfected with 50 μg of theappropriate GnRH receptor DNA construct by electroporation in a BTXElectroCell Manipulator ECM 600 (Fisher Scientific, Pittsburgh, Pa.)using the following settings: 1000 μF capacitance, 48Ω resistance, and300 V/cm charging voltage. Transfected cells are cultured for 36-48 hprior to membrane preparation. Transiently transfected COS-7 cells areharvested, washed, and resuspended in membrane buffer (20 mM HEPES pH7.2, 6 mM MgCl₂, 1 mM EDTA). Cells are centrifuged and the cell pelletsare resuspended in a small volume of membrane buffer. Cells are lysed byrelease of pressure following incubation at 900 psi for 30 minutes at 4°C. in a nitrogen chamber. The homogenate is centrifuged at 1000 g for 10minutes at 4° C. to remove nuclei and cellular debris. Membranes arecollected from the supernatant by centrifugation at 44,000 g for 45minutes at 4° C. Membranes are resuspended in membrane buffer at aconcentration of 1 mg/mL, quick-frozen in liquid nitrogen, and stored at−80° C. until used.

Radioligand Binding Assays

Radioligand binding displacement assays using the peptide radioligandsare performed in buffer containing 10 mM HEPES, 150 mM NaCl and 0.1%BSA, pH=7.5. Radioligand binding assays employing the use of[³H]-1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil(here the 3-methoxy group is tritiated) are run in buffer containing 50mM Tris, 150 mM NaCl, 5 mM MgCl₂, 0.01% saponin and 0.5 mM EDTA, pH=7.5.Radioligand displacement assays are performed by incubating radioligand([¹²⁵I-Tyr⁵,DLeu⁶,NMeLeu⁷, Pro-N Et]GnRH (0.1 nM), [His⁵, ¹²⁵I-DTyr]GnRH(0.2 nM) (31) or[³H]-1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil(1 nM)), unlabeled competitors at concentrations ranging from 0.3 pM to10 μM, and membranes for 2 hrs at rt. 10 to 20 μg protein/well is usedfrom membrane preparations for human, monkey and rabbit GnRH receptor. 5μg/well and 60 μg/well of membranes are used for rat and dog GnRHreceptors, respectively. Binding assays are performed in eitherMillipore 96-well GF/C filtration plates (for ([¹²⁵I-Tyr⁵,DLeu, NMeLeu⁷,Pro⁹-NEt]GnRH assays), or in 96 well low binding plates, which aresubsequently filtered onto GF/C Unifilters. Filters are pretreated with0.5% PEI for 30 min prior to use. Reactions are terminated by rapidvacuum filtration, and the filters are washed twice with 250 μL ice coldPBS pH=7.4 (0.01% Tween-20 is included in wash media for [His⁵,¹²⁵I-DTyr⁶]GnRH and[³H]-1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracilradioligands). The filters are dried, and the Millipore filters aremonitored for radioactivity using a Cobra II gamma counter (Perkin ElmerLife Sciences). For assays filtered onto the GF/C Unifilter plates, 50μL scintillation fluid is added to each filter, and radioactivity ismonitored using a TopCount NXT. For iodinated radioligands, totalradioligand is monitored on a gamma counter, and for the tritiatedradioligand, total radioligand is monitored using a Perkin Elmer 1600TRliquid scintillation counter. Total radioligand bound does not exceed10% of the total radioligand added, a level of depletion which does notappreciably affect the measurement of K_(i). Nonspecific binding doesnot exceed 2% of the total radioligand added in any of the displacementassays. Inhibition of radioligand binding is fit to one-site andtwo-site competition binding equations and the best fit determined usingan F-test. For all displacement binding experiments a single sitebinding model fit best (p<0.05). The K_(i) values are calculated fromthe IC₅₀ values using the method of Cheng and Prusoff (Biochem.Pharmacol. 22:3099, 1973) and may be converted to a pK_(i) value(negative log of the K_(i) value).

$K_{i} = \frac{{IC}_{50}}{1 + {L/K_{D}}}$where L=radioligand and K_(D)=affinity of radioligand for receptor. GnRHreceptor antagonists of this invention have a K_(i) of 10 μM or less. Inother embodiments of this invention, the GnRH receptor antagonists havea K_(i) of less than 1 μM, and in many instances have a K_(i) of lessthan 0.1 μM (i.e., 100 nM).

Compounds of the present invention as shown in Examples 2 to 52 below(not including chemical intermediates) which were tested in one or moreof the peptide competition human receptor binding assays shown haveK_(i) values of 1 μM or less. Additionally, the following compounds ofthe present invention as shown in Examples 2 to 52 below (not includingchemical intermediates) which were tested in one or more of the peptidecompetition human receptor binding assays shown have K_(i) values of 100nM or less, while the underlined compounds have K_(i) values of 10 nM orless: 2-1, 2-2, 2-3, 2-6, 2-8, 2-9, 2-10, 2-11, 2-12, 2-13, 2-14, 2-15,2-16, 2-18, 2-19, 2-21, 2-22, 2-24, 2-25, 2-26, 2-27, 2-2, 2-31, 2-33,2-34, 2-5, 2-36, 2-37, 2-39, 2-42, 2-45, 2-46, 2-48, 2-49, 2-50, 2-53,2-54, 2-55, 2-57, 2-58, 2-59, 2-60, 2-61, 2-62, 2-63, 2-64, 2-65, 2-66,2-67, 2-68, 2-69, 2-70, 2-71, 2-72, 2-75, 2-76, 2-77, 2-79, 2-80, 2-81,3-1, 3-2, 3-3, 3-4, 3-5, 3-8, 3-9, 3-10, 3-11, 3-12, 3-18, 3-19, 3-22,4-1, 4-2, 4-3, 4-4, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 5-1, 5-2,5-3, 5-4, 5-5, 5-6, 6-1, 7-1, 8-7, 9-5, 10-1, 10-2, 11-1, 11-2, 11-3,11-4, 11-5, 11-6, 11-7, 11-8, 13-3, 14-1, 14-2, 14-3, 14-4, 15-1, 16-1,16-2, 17-2, 18-1, 19-1, 19-2, 19-3, 19-5, 19-6, 19-7, 19-8, 19-9, 19-10,20-1, 20-2, 2-3, 21-1, 21-2, 21-3, 21-4, 21-5, 21-6, 21-7, 21-8, 22-1,22-2, 22-3, 22-4, 22-6, 22-7, 22-8, 22-9, 22-10, 23-1, 24-2, 26-1, 27-1,28-1, 30-2, 30-5, 30-7, 30-8, 30-9, 30-10, 30-11, 30-12, 30-13, 30-14,30-15, 30-16, 30-17, 31-1, 33-1, 33-2, 33-3, 34-1, 34-2, 34-3, 34-4,34-5, 34-6, 34-87, 34-9, 34-10, 34-11, 34-12, 34-13, 34-15, 34-16,34-17, 34-18, 34-19, 34-20, 34-23, 34-24, 34-25, 34-26, 35-1, 36-1, 362,37-1, 37-2, 37-3, 37-4, 38-1, 39-1, 39, 39-3, 39-4, 39-5, a 6, 39-7,39-8, 39-9, 39-10, 39-11, 39-12, 39-13, 3914, 39-15, 39-16, 39-17,39-18, 39-20, 39-21, 39-23, 40-1, 41-1, 42-1, 42-2, 42-3, 42-4, 42-5,42-6, 42-7, 42-8, 42-9, 42-10, 42-11, 42-12, 42-13, 42-14, 42-15, 42-16,42-17, 42-18, 43-1, 44-1, 45-1, 46-1, 46-2, 46-3, 46-4, 47-1, 47-2,47-3, 47-4, 47-5, 48-1, 48-2, 49-1, 49-2, 49-3, 49-4, 50-1, 50-2, 50-3,51-1, 52-1, 53-1, 53-2.

Wheat-germ agglutinin (WGA)-coupled polystyrene (PS) imaging beads(Amersham Biosciences, Piscataway, N.J.) are used in our scintillationproximity assay, permitting whole-plate light imaging with a CCD imagingsystem, as used by Viewlux (PerkinElmer Life Sciences, Boston, Mass.).Integrity of the receptor and radiolabel is monitored by saturationanalysis measured at each time point to ensure a consistent K_(d).Generally, the GnRH SPA assay produced reliable binding data up to 16 hof incubation. The optimal membrane/SPA bead ratio is determined foreach membrane preparation and is typically 40 μg membrane/0.5 mg beadper well. Typically, the instrument is set to measure luminescence for300 sec using a 613-nm filter to capture the red-shifted emission of theimaging beads and programmed to record at 60-min intervals for 11 h.

Reactions typically consist of 50 μL unlabeled compound variousconcentrations; 50 μL radiolabeled [¹²⁵I]-His⁵, D-Tyr⁶ GnRH ligand (˜300pM, 2200 Ci/mmol; PerkinElmer Life Sciences); and 100 μL membrane/SPAbead added sequentially in assay buffer (10 mM HEPES, 150 mM NaCl, 0.1%bovine serum albumin [BSA; Fraction V], pH 7.5) to low binding 96-wellplates (Corning, Palo Alto, Calif.). Cell membrane fractions wereprepared as previously described and resuspended in assay buffer.

SPA beads and membrane (rat basophilic leukemia [RBL] cells stablyexpressing human GnRH-R) are pre-incubated for 2 h prior to compound andradiolabel addition. The complete reaction is briefly shaken and allowedto settle at room temperature in the Viewlux instrument. The amount ofbound radioligand is determined at the indicated time intervals.

A single-site binding model is applied for all displacement bindingexperiments, as determined by a partial F test (p>0.05). Dose-responsecurves for both time points of all compounds tested are normalized tozero and 100% specific binding, and Ki values are calculated using theCheng-Prusoff equation with a sigmoidal dose-response fit using Prism4.0 software (GraphPad Software, San Diego, Calif.) using Kd values of0.2 nM for [¹²⁵I]-His⁵, D-Tyr⁶ GnRH, as determined from saturationbinding experiments. Hill slopes for all curves routinely range from−0.8 to −1.1.

Radioligand association experiments to estimate the affinity ofcompounds of the present invention may be initiated by the addition ofcell membranes to wells containing an appropriate amount of aradiolabeled tracer, in the absence and presence of a range ofconcentrations of compound (Sullivan et al., Biochemical Pharmacology,72, 2006, 838-849). All buffers are pre-heated to 37° C. prior toinitiation of experiment, and assay plates are maintained at thistemperature throughout the experiment. The assay mixture (total volumeof 200 μL) is incubated at 37° C. for 1 min to 3 hr (15 time points),and the assay is terminated by rapid vacuum filtration through a cellharvester (UniFilter-96 Filtermate; Packard, PerkinElmer Life Sciences)onto Unifilter GF/B filter plate pretreated with 0.5% polyethyleniminein distilled water for 30 min. After filtration, membranes are washedtwo times with 400 μL wash buffer (Dulbecco's Phosphate-Buffered Saline,0.01% Tween-20, pH 7.5). Filter plates are dried, 50 μL scintillationfluid is added (Microscint 20; PerkinElmer Life Sciences), and the plateis monitored for radioactivity using a TopCount NXT at 30% efficiency(PerkinElmer Life Sciences). The total amount of radioligand added tothe assay is measured using a 1600TR liquid scintillation counter(PerkinElmer Life Sciences) at 47% efficiency. Analyses are performedusing Prism 4.1 Software (GraphPad Software, San Diego, Calif.).

Ca⁺⁺ Flux Measurement

To determine the inhibition of GnRH-stimulated calcium flux in cellsexpressing the human GnRH receptor, a 96-well plate is seeded with RBLcells stably transfected with the human GnRH receptor at a density of50,000 cells/well and allowed to attach overnight. Cells were loaded for1 hour at 37° C. in the following medium: DMEM with 20 mM HEPES, 10%FBS, 2 μM Fluo-4, 0.02% pluronic acid and 2.5 mM probenecid. Cells arewashed 4 times with wash buffer (Hanks balanced salt, 20 mM HEPES, 2.5mM probenecid) after loading, leaving 150 μL in the well after the lastwash. GnRH is diluted in 0.1% BSA containing FLIPR buffer (Hanksbalanced salt, 20 mM HEPES) to a concentration of 20 nM and dispensedinto a low protein binding 96-well plate. Various concentrations ofantagonists are prepared in 0.1% BSA/FLIPR buffer in a third 96-wellplate. Cell, agonist, and antagonist containing plates are loaded into aflurometric imaging plate reader (FLIPR) (Molecular Devices, FLIPR384system, Sunnyvale, Calif.) for liquid handling and fluorescencemeasurements according to manufacturer's instructions. The instrument isprogrammed such that antagonist (50 μL at varying concentrations) isadded to cell plates and preincubated for 1 minute prior to addition ofagonist (50 μL, or 4 nM final concentration of GnRH).

Measurement of [³H]IP Production

The procedure is modified from published protocols (Zhou et al., J.Biol. Chem. 270:18853-57 (1995)). Briefly, RBL cells stably transfectedwith human GnRH receptors are seeded in 24 well plates at a density of200,000 cell/well for 24 hours. Cells are washed once with inositol-freemedium containing 10% dialyzed FBS and then labeled with 1 μCi/mL of[myo-³H]inositol. After 20-24 hours, cells are washed with buffer (140mM NaCl, 4 mM KCl, 20 mM Hepes, 8.3 mM glucose, 1 mM MgCl₂, 1 mM CaCl₂and 0.1% BSA) and treated with native GnRH peptide in the same bufferwith or without various concentrations of antagonist and 10 mM LiCl for1 hour at 37° C. Cells are extracted with 10 mM formic acid at 4° C. for30 min and loaded to the Dowex AG1-X8 column, washed and eluted with 1 Mammonium formate and 0.1 M formic acid. The eluate is counted in ascintillation counter. Data from PI hydrolysis assay are plotted usingnon-linear least square regression by Prism program (GraphPad Software,San Diego, Calif.), from which dose ratio is also calculated. The Schildlinear plot is generated from the dose-ratios obtained in fourindependent experiments by linear regression, the X-intercept is used todetermine the affinity of the antagonist.

Activation of ERK1/2

CHO cells stably expressing GnRH receptor are serum-starved for 1 hour,incubated for 5 min with various doses of antagonist, and stimulatedwith 1 nM GnRH for 5 min at 37° C. Cells are washed once with PBS andharvested directly into 2×SDS sample buffer. Cell extracts aresonicated, heated at 55° C. for 5 min, and subjected to SDS-PAGE.Resolved proteins are transferred onto nitrocellulose membranes. Theactivated phosphorylated form of ERK1/2 is detected using ananti-phosphoMAPK p42/44 antibody (Cell Signaling Technology, Danvers,Mass.) diluted at 1:3000 in 1% nonfat dried milk in TBST (20 mMTris-HCl, pH 7.4, 137 mM NaCl, 0.1% Tween20). Total ERK1/2 is detectedwith the anti-ERK2 antibody (K23, Santa Cruz Biotechnology, Santa Cruz,Calif.). Chemiluminescent detection is performed with SuperSignal WestPico reagent (Pierce, Rockford, Ill.) and quantified on the VersaDoc3000(Bio-Rad) imaging system. Dose-response data are plotted and analyzedwith GraphPad Prism software.

Histamine Release

Rat peritoneal mast cells are obtained in accordance with the currentNIH guidelines for the humane and ethical use of laboratory animals andanimal welfare, and under an IACUC approved protocol. This method hasbeen previously described for the evaluation of mast cell histaminerelease by peptide GnRH antagonists (Sundarem et al., Agents Actions25:307-13 (1988)). Briefly, six male Sprague Dawley rats 240-300 g aresacrificed by CO₂ asphyxiation and 40 mL of cold PIPES buffer (25 mMPIPES, 110 mM NaCl, 5 mM KCl, 1 mg/mL glucose, 1 mg/mL BSA and 20 U/mLheparin, pH 7.4) is injected into the peritoneal cavity and the abdomenmassaged gently. Peritoneal wash is recovered and stored on ice. Cellsfrom the peritoneal wash are washed 3 times with 5 mL PIPES buffer,pooled and purified on a Percoll gradient (Wells and Mann, Biochem.Pharmacol. 32:837-42 (1983)). For stimulation assays, approximately2×10⁵ cells in 300 μL PIPES buffer are placed into a 1.5 mL eppendorftube and test compound (100 μL) is added to the cell suspension. Thetubes are incubated at 37° C. for 15 min and the reaction is stoppedwith 600 μl of ice-cold PIPES buffer. After centrifugation at 4° C., thehistamine level in the supernatant is determined by histamine EIA kitfrom SPI-BIO (Cayman Chemical, Ann Arbor, Mich.) followingmanufacturer's instructions.

LH Suppression in Castrated Macaques

This study in macaques is conducted in accordance with the current NIHguidelines for the humane and ethical use of laboratory animals andanimal welfare, and under an IACUC approved protocol. A completeorchiectomy (both testes) is performed approximately 4 weeks prior tothe first dose on male cynomolgus monkeys approximately 3.7 to 6.5 yearsof age (3.7 to 4.8 kg). Sexual maturity is verified by testicular volumeand testosterone levels prior to surgery. Blood samples are collectedweekly during the 4-week post-surgery recovery period for measurement oftestosterone, FSH and LH to verify the rise in gonadotropins. Antagonistis administered to the stomach by nasogastric gavage or by i.v. infusion(over ˜15 minutes). Blood samples are collected prior to and after eachdose for analysis of serum LH and plasma antagonist concentrations. Forthe intravenous infusion dose, samples are collected at 0.25, 0.33, 0.5,1, 1.5, 4, 8, and 24 hours after the initiation of the infusion. Samplesare collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, and 24 hours postdose forthe oral doses. Bioactive LH concentrations in serum samples aremeasured at the Oregon Regional Primate Center (Beaverton, Oreg.) or theYerkes Primate Research Center at Emory University using a previouslyreported mouse Leydig cell bioassay, which detects as little as 3 ngLH/mL using cynomolgus LH RP-1 as the reference preparation (Ellenwoodand Resko, Endocrinology 107:902-907 (1980)).

As mentioned above, the GnRH receptor antagonists of this invention mayhave utility over a wide range of therapeutic applications, and may beused to treat a variety of sex-hormone related conditions in both menand women, as well as mammals in general. For example, such applicationsinclude endometriosis, uterine fibroids, polycystic ovarian disease,dysmenorrhea, dyspareunia, menorrhagia, nonmenstrual pelvic pain, pelvictenderness, induration, general disorders of the menstrual cycle,premature ovarian failure due to chemotherapy or early menopause,hirsutism, precocious puberty, gonadal steroid-dependent neoplasia suchas cancers of the prostate, breast and ovary, gonadotroph pituitaryadenomas, adenomyosis sleep apnea, irritable bowel syndrome,premenstrual syndrome, benign prostatic hypertrophy, lower urinary tractsymptoms (LUTS), contraception and infertility (e.g., assistedreproductive therapy such as in vitro fertilization). The compounds ofthis invention may also be useful as an adjunct to treatment of growthhormone deficiency and short stature, and for the treatment of systemiclupus erythematosis.

In addition, the compounds may be useful in combination with androgens,estrogens, progesterones, antiestrogens, antiprogestogens,angiotensin-converting enzyme inhibitors, angiotensin II-receptorantagonists, renin inhibitors, bisphosphonates and other agents for thetreatment and/or prevention of disturbances of calcium, phosphate andbone metabolism, aromatase inhibitors, analgesics such as non-steroidalanti-inflamatory drugs (NSAIDS), other COX inhibitors, and anti-NGFagents.

In another embodiment of the invention, pharmaceutical compositionscontaining one or more GnRH receptor antagonists are disclosed. For thepurposes of administration, the compounds of the present invention maybe formulated as pharmaceutical compositions. Pharmaceuticalcompositions of the present invention comprise a GnRH receptorantagonist of the present invention and a pharmaceutically acceptablecarrier and/or diluent. The GnRH receptor antagonist is present in thecomposition in an amount which is effective to treat a particulardisorder—that is, in an amount sufficient to achieve GnRH receptorantagonist activity, and preferably with acceptable toxicity to thepatient. Appropriate concentrations and dosages can be readilydetermined by one skilled in the art.

Pharmaceutically acceptable carrier and/or diluents are familiar tothose skilled in the art. For compositions formulated as liquidsolutions, acceptable carriers and/or diluents include saline andsterile water, and may optionally include antioxidants, buffers,bacteriostats and other common additives. The compositions can also beformulated as pills, capsules, granules, or tablets which contain, inaddition to a GnRH receptor antagonist, diluents, dispersing and surfaceactive agents, binders, and lubricants. One skilled in this art mayfurther formulate the GnRH receptor antagonist in an appropriate manner,and in accordance with accepted practices, such as those disclosed inRemington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co.,Easton, Pa. 1990.

In another embodiment, the present invention provides a method fortreating sex-hormone related conditions as discussed above. Such methodsinclude administering of a compound of the present invention to awarm-blooded animal in an amount sufficient to treat the condition. Inthis context, “treat” includes prophylactic administration. Such methodsinclude systemic administration of a GnRH receptor antagonist of thisinvention, preferably in the form of a pharmaceutical composition asdiscussed above. As used herein, systemic administration includes oraland parenteral methods of administration.

For oral administration, suitable pharmaceutical compositions of GnRHreceptor antagonists include powders, granules, pills, tablets,lozenges, chews, gels, and capsules as well as liquids, syrups,suspensions, elixirs, and emulsions. The compounds of the invention mayalso be used in fast dissolving, fast disintegrating dosage forms. Thesecompositions may also include anti-oxidants, flavorants, preservatives,suspending, thickening and emulsifying agents, colorants, flavoringagents and other pharmaceutically acceptable additives. Formulations fororal administration may be formulated to be immediate release ormodified release, where modified release includes delayed, sustained,pulsed, controlled, targeted and programmed release.

For parenteral administration, the compounds of the present inventionare administered directly into the blood stream, into muscle, or into aninternal organ via an intravenous, intraarterial, intraperitoneal,intramusclar, subcutaneous or other injection or infusion. Parenteralformulations may be prepared in aqueous injection solutions which maycontain, in addition to the GnRH receptor antagonist, buffers,antioxidants, bacteriostats, salts, carbohydrates, and other additivescommonly employed in such solutions. Parenteral administrations may beimmediate release or modified release (such as an injected or implanteddepot).

Compounds of the present invention may also be administered topically,(intra)dermally, or transdermally to the skin or mucosa. Typicalformulations include gels, hydrogels, lotions, solutions, creams,ointments, dressings, foams, skin patches, wafers, implants andmicroemulsions. Compounds of the present invention may also beadministered via inhalation or intanasal administration, such as with adry powder, an aerosol spray or as drops. Additional routes ofadministration for compounds of the present invention includeintravaginal and rectal (by means of a suppository, pessary or enema),and ocular and aural.

For administration to human patient (or subject), the total daily doseof the compounds of the present invention may be in the range of 1 to500 mg, typically 5 to 300 mg, more typically 25 to 250 mg, depending,of course on a number of factors including age, sex, and weight of asubject and also on the mode of administration. The total daily dose maybe administered singly or in divided doses.

The following examples are provided for purposes of illustration, notlimitation. In summary, the GnRH receptor antagonists of this inventionmay be assayed by the general methods disclosed above, while thefollowing Examples disclose the synthesis of representative compounds ofthis invention.

EXAMPLES

HPLC Methods for Analyzing the Samples

Retention time, t_(R), in minutes

Method 1: Column: Synergi 4μ, Max-RP 80A, 50×2 mm; Gradients: from 95%H₂O+0.025% TFA/MeCN to 95% MeCN+0.025% TFA/H₂O over 3 min;

Flow rate: 1 mL/min; UV: 222 and 254 nM

Method 2: Column: Synergi 4μ, Max-RP 80A, 50×2 mm; Gradients: from 95%H₂O+0.025% TFA/MeCN to 95% MeCN+0.025% TFA/H₂O over 13 min;

Flow rate: 1 mL/min; UV: 222 and 254 nM

Method 3: Column: Phenomenex 5μ, Gemini C18 110A, 150×4.6 mm

Gradients: from 95% H₂O+0.04% NH₄OH to 90% MeCN+0.04% NH₄OH over 9.86min.

Flow rate: 2.5 mL/min. UV: 222 and 254 nM

Method 4: Column: Phenomenex 4μ, RP 80A, 50×2 mm

Gradients: from 95% [H₂O+10 mM NH₄CHO]; 5% [25% MeCN in MeOH] to 5%[H₂O+10 mM NH₄CHO] over 6.43 min.

Flow rate: 1 mL/min. UV: 222 and 254 nM

Method 5: Column: Waters Xterra RP, 250×3 mm

Gradients: from 90% [H₂O+0.025% TFA] to 95% [MeCN+0.025% TFA] over 46min.

Flow rate: 0.8 mL/min. UV: 222 and 254 nM

Example 1 5-Bromo-2-trifluoromethyl-isonicotinonitrile

Step 1A: 5-Bromo-2-trifluoromethyl-isonicotinic Acid

To a 100 mL round bottom flask equipped with a rubber septa and nitrogeninlet was charged 5 g (22.1 mmol) of 5-bromo-2-trifluoromethylpyridine.To the solid was charged 30 mL of anhydrous THF under a nitrogenatmosphere. After the solution became homogeneous, it was chilled with a−78° C. dry ice/acetone bath. To a separate 100 mL round bottom flaskequipped with a rubber septa and nitrogen inlet was charged 3.4 mL (24.2mL, 1.1 eq) of anhydrous diisopropyl amine. To the solution was charged16.9 mL of anhydrous THF, placed under a nitrogen atmosphere and chilledwith an ice bath. To the solution was carefully added 9.7 mL (24.3 mmol,1.1 eq) of 2.5 M n-butyl lithium in hexanes. The light yellow LDAsolution was chilled with a −78° C. dry ice/acetone bath. A 100 mL pearshaped flask equipped with a rubber septa, nitrogen inlet, stir bar,thermocouple and double headed cannula needle was placed under anitrogen atmosphere and chilled with a −78° C. dry ice/acetone bath. Toa 250 mL round bottom flask equipped with a rubber septa, CO₂ inlet,needle outlet and stir bar was charged 30 mL of anhydrous THF. Thesolution was chilled with a −78° C. dry ice/acetone bath and anhydrousCO₂ bubbled through the solution for 10 minutes.

To the empty 100 mL flask was charged 5 mL of the LDA solution. To thiswas charged 5 mL of the 5-bromo-2-trifluoromethylpyridine solution atsuch a rate to keep the solution temperature<−60° C. Upon addition, themixture was stirred for 1 minute then transferred via cannula underpositive nitrogen pressure to the CO₂ saturated solution. This affordeda light maroon solution. The process was repeated until all startingmaterials were transferred to the CO₂ solution. The CO₂ solution wasallowed to stir with a −78° C. dry ice/acetone bath for 1 hour. Thecooling bath was removed and the solution allowed to warm to ambienttemperature.

To the reaction mixture was carefully added 150 mL of saturated ammoniumchloride solution. The mixture was transferred to a 500 mL separatoryfunnel. The lower aqueous phase was separated and the organic phaseextracted with 100 mL of 1N sodium hydroxide solution. The combinedaqueous phases were extracted with 100 mL of MTBE. The aqueous phase wasacidified to ˜pH 1 with concentrated hydrochloric acid. The cloudyaqueous mixture was extracted twice with 200 mL of MTBE. The combinedorganic phases were washed once with 100 mL of brine, dried overmagnesium sulfate, filtered and concentrated in vacuo to afford5-bromo-2-trifluoromethyl-isonicotinic acid (4.7 g) as an off-whitesolid in a 78% yield.

Step 1B: 5-Bromo-2-trifluoromethyl-isonicotinamide

To a 500 mL round bottom flask equipped with a stir bar, condenser andnitrogen inlet was charged 38.9 g (144 mmol) of5-bromo-2-trifluoromethyl-isonicotinic acid. To the solid was charged250 mL of anhydrous dichloromethane followed by 13.2 mL (151 mmol, 1.05eq) oxalyl chloride. To the mixture was added 0.5 mL of anhydrousdimethylformamide and the mixture was stirred at ambient temperature for2 h. The reaction was complete as evidenced by HPLC (methanol quench ofaliquot). The solvent was removed in vacuo affording an amber oil.

To a 1 L Erlenmeyer flask equipped with a stir bar in an ice-bath wascharged 500 mL of aqueous ammonium hydroxide. To the chilled solutionwas added dropwise the crude acid chloride. The residue was transferredwith a small amount of acetonitrile. The mixture was stirred for 20minutes following addition. The resulting precipitate was collected byfiltration and washed with water. The filter cake was dried in vacuo at45° C. affording 31.8 g of 5-bromo-2-trifluoromethyl-isonicotinamide asan off-white solid in a 82% yield. The compound may also be purifiedusing an ether slurry and collecting the solid.

Step 1C: 5-Bromo-2-trifluoromethyl-isonicotinonitrile

To a 100 mL round bottom equipped with a stir bar, condenser andnitrogen inlet was charged 5.2 g (19.3 mmol) of5-bromo-2-trifluoromethyl-isonicotinamide. The solid was diluted with 12mL of phosphorus oxychloride. The mixture was heated at 70° C. for 3 hr.The mixture was cooled to ambient temperature and poured onto ice. Themixture was neutralized with the careful addition of 50% sodiumhydroxide. The resulting off-white solid was collected by filtration,washed with water and dried in vacuo at 50° C. for 18 h. This afforded4.5 g of 5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1 as anoff-white solid in a 94% yield. ¹HNMR (CDCl₃), δ, 9.03 (s, 1H), 7.91 (s,1H).

5-Bromo-4-methyl-2-(trifluoromethyl)pyridine

Step 1E: 5-Bromo-4-methyl-2-(trifluoromethyl)pyridine

In a dried 250 mL 3-neck round bottom flask fitted with a stirrer bar,thermometer, and flushed with nitrogen, was placed anhydrous THF (16 mL,Aldrich, inhibitor free) followed by N, N-diisopropylamine (0.895 g,8.85 mmol, Aldrich, redistilled 99.95% pure). After cooling the stirredsolution to −70° C., n-butyl lithium (3.54 mL of a 2.5M solution inhexanes, 8.85 mmol) was added dropwise, keeping the reaction temperatureless than −60° C. The resulting solution was stirred at −70° C. for afurther 10 min, then warmed to −20° C., before immediately cooling to−90° C. A solution of 5-bromo-2-(trifluoromethyl)pyridine (2 g, 8.85mmol) in anhydrous THF (8 mL, Aldrich, inhibitor free) was addeddropwise, keeping the reaction temperature less than −85° C. Theresulting orange solution was stirred at −90° C. for 40 min.

In a separate dried 250 mL 3-neck round bottom flask fitted with astirrer bar, thermometer, and flushed with nitrogen, was placedanhydrous THF (5 mL, Aldrich, inhibitor free) followed by methyl iodide(5 mL, 80 mmol). The solution was cooled to −90° C. To this was added(via cannula) the solution of the pre-formed lithiated pyridine,controlling the rate so as to keep the reaction temperature of thereceiving flask less than −80° C. The resulting dark solution wasstirred at −90° C. for a further 15 min (LCMS indicated reactioncomplete). The reaction was quenched with sat aq. NH₄Cl solution (50mL), then allowed to slowly warm to room temperature. Organics wereextracted with EtOAc (2×50 mL), then the combined organic layers washedwith water (50 mL), then brine (50 mL), separated, dried over MgSO₄, andthen filtered. Concentration in vacuo gave 1.68 g of a brown oil whichwas purified via short-path vacuum distillation (45-46° C., ca. 5 mmHg)to give 5-bromo-4-methyl-2-(trifluoromethyl)pyridine 1-2 (0.289 g, 14%)as a yellow oil (>97% pure). MS (M+H)⁺: 241.8, t_(R)=2.458 min (method1); ¹H NMR (CDCl₃) δ 8.74 (1H, s), 7.56 (1H, s), 2.50 (3H, s).

5-Bromo-2-cyano-4-methylpyridine

Step 1F: 2,5-Dibromo-4-methylpyridine

2-Amino-5-bromo-4-methylpyridine (2.0 g, 10.7 mmol) was dissolved in 48%aqueous HBr (14 mL, 123 mmol) and cooled to 2° C. in a salt/ice bath.Bromine (1.65 mL, 32.1 mmol) was added dropwise keeping the internaltemperature below 2° C. A solution of sodium nitrite (3.69 g, 53.5 mmol)in water (5 mL) was added keeping the internal temperature below 5° C.and stirred for 1 h between 0° C. and 5° C. The pH was adjusted to ˜13by slow addition with cooling of 50% NaOH (aq). After warming to r.t.the reaction was extracted with ether, the organics were dried overMgSO₄ and concentrated to give a brown oil. Flash chromatography onsilica gel eluting with 5% ether/hexane gave the product as a whitesolid (1.83 g, 7.29 mmol, 68%). MS [M+H]⁺: 251.9; t_(R)=2.3 min. (method1)

Step 1: (5-Bromo-4-methylpyridin-2-yl)-N-t-butyl carboxylic amide

2,5-Dibromo-4-methylpyridine (1.83 g, 7.29 mmol) was dissolved intoluene (100 mL), cooled to −78° C. and a solution of nBuLi (4.4 mL, 8.8mmol, 2.0 M in pentane) was added dropwise and stirred at −78° C. for 2h. A solution of tBuNCO (1.1 mL, 9.5 mmol) in toluene (3 mL) was addeddropwise and stirred for 1 h at −78° C. then warmed to −10° C. andquenched by addition of NH₄Cl (aq). After warming to r.t. the reactionwas extracted with ether and the organics dried over Na₂SO₄ andconcentrated. The product was used without further purification. MS[M+H]⁺: 271.0; t_(R)=2.44 min. (method 1)

Step 1H: 5-Bromo-2-cyano-4-methylpyridine

This material was dissolved in toluene (10 mL). POCl₃ (10 mL) was addedand the solution refluxed for 5 h. After cooling to room temperature thesolvents were removed in vacuo, the reaction was basified by addition of2 M NaOH (aq) and extracted with ether. The organic extract was washedwith brine, dried over MgSO₄ and concentrated. Chromatography on silicagel eluting with 20% EtOAc/Hexane gave 5-bromo-2-cyano-4-methylpyridine1-3 as an off-white crystalline solid (920 mg, 4.7 mmol, 64% over 2steps). ¹H NMR (300 MHz, CDCl₃) 8.73 (1H, s), 7.56 (1H, s), 2.46 (3H,s). MS [M+H]⁺: 196.8.0; t_(R)=2.04 min. (method 1).

2-Bromo-3,5-dichloro-6-methylpyridine

Step 11: 2-Bromo-3,5-dichloro-6-methylpyridine

2-Amino-3,5-dichloro-6-methylpyridine (3.54 g, 20 mmol) was suspended inaqueous 48% HBr solution at room temperature and the mixture was cooledto −20° C. This suspension was maintained at −20° C. while bromine (2.87mL, 56 mmol) was added dropwise. The resultant paste was stirred for 30minutes at this temperature before the dropwise addition of a cooledsolution of sodium nitrite (3.59 g, 52 mmol) in water (5 mL). At thispoint the reaction mixture was allowed to warm to room temperature.After stirring for a further 60 minutes, the mixture was again cooled to−20° C. and treated with a solution of sodium hydroxide (16 g, 0.4 mol)in water (20 mL). This mixture was extracted with ethyl acetate and theorganic layer washed with water and then brine solution. The organicsolution was dried over MgSO₄, filtered and the residue obtained fromsolvent evaporation was purified using silica gel chromatography[eluent: 10% ethyl acetate in hexane].2-Bromo-3,5-dichloro-6-methylpyridine 1-4 (2.14 g, 45%) was obtained asa solid.

5-Bromo-4-chloro-2-methyl-pyridine

Step 1J: 5-Bromo-2-methyl-4-nitropyridine Oxide

A mixture of 5-bromo-2-methyl-pyridine (10.0 g, 58.0 mmol), hydrogenperoxide (28 mL, 30% in water) in acetic acid (28 mL) was heated to 90°C. for 2 days, then additional hydrogen peroxide (14 mL) was added. Themixture was heated for another 1 day. Upon cooling to room temperature,it was extracted with CHCl₃ three times. The organic solution was thendried over MgSO₄, and concentrated to yield the crude pyridine oxide.MS: 187.7 (M+H)⁺; t_(R)=2.22 min. (method 1).

The above pyridine oxide was added into a mixture of HNO₃ (18 mL) andH₂SO₄ (16 ml) at 0° C. The mixture was then heated to 90° C. for 48 hrs,allowed to cool to room temperature and poured into iced water resultingin a precipitation. The solid was filtered and dried to afford5-bromo-2-methyl-4-nitropyridine oxide (7.32 g). MS: 232.7 (M+H)⁺;t_(R)=1.94 min. (method 1).

Step 1K: 5-Bromo-4-chloro-2-methylpyridine

5-Bromo-2-methyl-4-nitropyridine oxide (7.0 g, 30 mmol) was refluxed inconc. HCl (80 mL) for 16 hrs. The mixture was allowed to cool to roomtemperature, partially concentrated and then neutralized by NaOH (10N)to pH 7. The crude was partitioned between CHCl₃ and water. The organicsolution was separated, dried and concentrated to yield5-bromo-4-chloro-2-methylpyridine oxide as a white solid (6.71 g). MS[M+H]⁺: 223.7; t_(R)=1.91 min. (method 1).

To the solid (6.71 g, 30 mmol) in CHCl₃ (60 mL) at 0° C., was addedPOCl₃ (7.85 mL, 90 mmol) slowly. The mixture was heated to reflux for 3hrs and allowed to cool to room temperature. The product was extractedby CHCl₃. The extracted solution was washed with sat. NaHCO₃, water anddried over MgSO₄. The filtrate was then concentrated to yield5-bromo-4-chloro-2-methylpyridine 1-5 as a yellow oil (5.9 g). MS[M+H-Cl]⁺: 171.9; t_(R)=2.13 min. (method 1)

Example 24-Chloro-3-(6-chloro-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide

Step 2A: 3-Bromo-4-chloro-benzoyl Chloride

To 3-bromo-4-chloro-benzoic acid (9.4 g, 40 mmol) in dry DCM (100 mL),was added DMF (0.5 mL) followed by addition of oxalyl chloride (22.5 mL,55 mmol, 2M in DCM) slowly. The mixture was stirred for 1 hr, thenconcentrated to yield 3-bromo-4-chloro-benzoyl chloride as an off-whitesolid.

Step 2B: 3-Bromo-4-chloro-N-(2-methoxy-phenyl)-benzamide

3-Bromo-4-chloro-benzoyl chloride in DCM (200 mL) was cooled in an icebath and triethylamine (11.1 mol, 80 mmol) was added slowly, followed bythe drop-wise addition of o-anisidine (4.5 mL, 40 mmol) in DCM (50 mL).At this time the ice bath was removed and the mixture was stirred for 12hrs, followed by partition between DCM and water. The organic layer waswashed with 1 N HCl, saturated NaHCO₃, brine and dried over MgSO₄.Concentration of the filtrate yielded3-bromo-4-chloro-N-(2-methoxy-phenyl)-benzamide as a pinkish solid (13.5g).

Step 2C: 3-Bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-benzamide

To 3-bromo-4-chloro-N-(2-methoxy-phenyl)-benzamide (13.5 g, 39 mmol) inDMF (100 mL) at 0-5° C., was added NaH (1.9 g, 46.8 mmol, 60% in mineraloil) in several portions, followed by addition of iodomethane (3.15 mL,50.7 mmol). The mixture was stirred at room temperature for 4 hrs andwas partitioned between ethyl acetate and water. The organic layer wasthen washed with 1N HCl, saturated NaHCO₃, brine and dried over MgSO₄.Filtration over a silica gel pad followed by concentration andcrystallization from ether/hexane yielded3-bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-benzamide (10.9 g) as awhite solid. MS (M+H)⁺: 353.9, t_(R)=2.812 min (method 1); NMR (CDCl₃),δ, 7.62 (1H, d, J=1.5 Hz), 7.23-7.09 (3H, m), 7.06-7.00 (1H, m),6.88-6.78 (2H, m), 3.75 (3H, s), 3.34 (3H, s)

Step 2C.1: 3-Bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-benzamide(Alternate Synthesis)

To 3-bromo-4-chloro-benzoyl chloride (5.4 g, 21.4 mmol) in DCM (100 mL)cooled with an ice bath, was added methoxy-N-methylaniline (3.2 g, 23.4mmol), followed by addition of triethylamine (5.9 mL, 42.5 mmol) slowly.Upon the completion of the addition, the ice bath was removed and themixture was stirred at room temperature for 12 hrs, followed bypartition between DCM and water. The organic layer was then washed with1 N HCl, saturated NaHCO₃, brine and was dried over MgSO₄. Concentrationand purification by silica gel column chromatography eluting withhexane/ethyl acetate (4/1) yielded3-bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-benzamide (5.1 g) as asolid.

Step 2D:4-Chloro-N-(2-methoxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide

To 3-bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-benzamide (9.7 g, 27.4mmol) in dioxane (150 mL), were added bis(pinacolato)diboron (10.4 g,41.1 mol), potassium acetate (8.05 g, 82.2 mmol) and Pd(dppf)₂Cl₂.CH₂Cl₂ (1.1 g, 1.35 mmol). The mixture was bubbled with N₂ for 10 minand then heated under N₂ at 80° C. for 24 hrs. The mixture was cooled toroom temperature, filtered through a silica gel pad, then concentrated.The resulting oil was purified by silica gel column chromatographyeluting with ethyl acetate in hexanes from 20% to 30% to yield4-chloro-N-(2-methoxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(10.7 g). NMR (CDCl₃), δ, 7.66 (1H, d, J=2.4 Hz), 7.32-7.23 (1H, m),7.17-7.07 (2H, m), 7.02-6.95 (1H, m), 6.82-6.74 (2H, m), 3.74 (3H, s),3.33 (3H, s), 1.30 (12H, s).

Step 2E:4-Chloro-3-(6-chloro-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide2-1

A mixture of toluene (1.5 mL) and water (0.5 mL) containing4-chloro-N-(2-methoxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(60 mg, 0.15 mmol), 5-bromo-2-chloro-pyridine (29 mg, 0.15 mmol),Pd(PPh₃)₄ (12 mg, 0.01 mmol), Na₂CO₃ (2N, 0.15 mL, 0.3 mmol), wasbubbled with N₂ for 5 min, then heated at 100° C. for 12 hrs. Themixture was filtered and purified by prep. LCMS to yield4-chloro-3-(6-chloro-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide2-1 (22.6 mg). MS: 386.7 (M+H)⁺; t_(R)=7.77 min (method 2).

Step 2E.1:4-Chloro-3-(6-chloro-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide(Alternate Synthesis)

A mixture of4-chloro-N-(2-methoxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(60 mg, 0.15 mmol), 5-bromo-2-chloro-pyridine (29 mg, 0.15 mmol),Pd(PPh₃)₄ (12 mg, 0.01 mmol), K₂CO₃ (41 mg, 0.3 mmol) in dioxane (1 mL),was heated at 100° C. for 12 hrs. The mixture was filtered and purifiedby prep. LCMS to yield4-chloro-3-(6-chloro-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide2-1.

The following compounds were prepared according to the proceduresdescribed above.

MS HPLC Ex. A (M + H)⁺ t_(R) (min) Method 2-1 6-methyl-pyridin-3-yl366.8 4.45 2 2-2 6-cyano-pyridin-3-yl 377.7 7.32 2 2-34,6-dichloro-pyridin-3-yl 422.9 8.32 2 2-42-chloro-6-methyl-pyridin-3-yl 400.7 7.47 2 2-52,6-dimethyl-pyridin-3-yl 380.8 4.30 2 2-6 2,6-dichloro-pyridin-3-yl420.7 8.43 2 2-7 6-methoxy-4-methyl-pyridin-3-yl 397.0 7.38 2 2-84-chloro-6-methyl-pyridin-3-yl 401.0 6.31 2 2-94,6-dimethyl-pyridin-3-yl 380.8 4.23 2 2-106-cyano-4-methyl-pyridin-3-yl 392.0 7.38 2 2-116-trifluoromethyl-pyridin-3-yl 420.7 9.63 3 2-124-methyl-6-trifluoromethyl-pyridin-3- 434.9 9.81 3 yl 2-136-chloro-4-methyl-pyridin-3-yl 410.5 8.23 2 2-144-cyano-6-trifluoromethyl-pyridin-3- 446.0 8.26 2 yl

            Ex.             A

          MS (M + H)⁺           t_(R) (min)           HPLC Method 2-156-chloro-pyridin-3-yl 2-methyl-phenyl 370.9 9.04 3 2-164-chloro-6-methyl- 2-methyl-phenyl 384.8 6.57 2 pyridin-3-yl 2-172-chloro-6-methyl- 2-methyl-phenyl 386.7 7.77 2 pyridin-3-yl 2-186-chloro-4-methyl- 2-methyl-phenyl 384.8 8.23 2 pyridin-3-yl 2-194-chloro-6-methyl- 2,6-dimethyl-phenyl 398.7 6.91 2 pyridin-3-yl 2-202-chloro-6-methyl- 2,6-dimethyl-phenyl 398.7 8.09 2 pyridin-3-yl 2-214-chloro-2,6- 2,3-dimethyl-phenyl 413.0 5.87 2 dimethyl-pyridin-3-yl2-22 4-chloro-6-methyl- 2,3-dimethyl-phenyl 398.8 7.04 2 pyridin-3-yl2-23 2-chloro-6-methyl- 2,3-dimethyl-phenyl 398.8 8.12 2 pyridin-3-yl2-24 4-chloro-6-methyl- 2-methyl-3- 452.7 7.61 2 pyridin-3-yltrifluoromethyl-phenyl 2-25 4-chloro-2,6- 2-methyl-3- 466.7 6.56 2dimethyl-pyridin-3-yl trifluoromethyl-phenyl 2-26 6-methoxy-4-methyl-2-methoxy-6-methyl- 411.1 9.64 3 pyridin-3-yl phenyl 2-274-chloro-6-methyl- 2-methoxy-6-methyl- 414.9 9.13 3 pyridin-3-yl phenyl2-28 2,6-dimethyl-pyridin- 2-methoxy-6-methyl- 395.7 8.60 3 3-yl phenyl2-29 4,6-dichloro-pyridin- 2-methoxy-6-methyl- 437.1 10.21 3 3-yl phenyl2-30 2-chloro-4-methyl- 2-methoxy-6-methyl- 416.7 7.66 2 pyridin-3-ylphenyl 2-31 6-chloro-4-methyl- 2-methoxy-6-methyl- 414.8 8.32 2pyridin-3-yl phenyl 2-32 6-trifluoromethyl- 2-methoxy-6-methyl- 435.09.96 3 pyridin-3-yl phenyl 2-33 4-methyl-6- 2-methoxy-6-methyl- 449.410.11 3 trifluoromethyl- phenyl pyridin-3-yl 2-34 6-cyano-4-methyl-2-methoxy-6-methyl- 406.0 7.73 2 pyridin-3-yl phenyl 2-35 4-cyano-6-2-methoxy-6-methyl- 459.9 9.81 3 trifluoromethyl- phenyl pyridin-3-yl2-36 6-chloro-4-methyl- 2-fluoro-phenyl 388.7 8.10 2 pyridin-3-yl 2-374-chloro-6-methyl- 2-fluoro-phenyl 388.8 6.46 2 pyridin-3-yl 2-384-chloro-2,6- 2-fluoro-phenyl 402.7 5.46 2 dimethyl-pyridin-3-yl 2-396-bromo-4-methyl- 2-fluoro-phenyl 434.9 8.13 2 pyridin-3-yl 2-404-chloro-6-methyl- phenyl 370.8 6.16 2 pyridin-3-yl 2-41 4-chloro-2,6-phenyl 384.8 5.24 2 dimethyl-pyridin-3-yl 2-42 6-chloro-4-methyl-3-chloro-2-methoxy- 436.9 7.90 2 pyridin-3-yl phenyl 2-432,6-dimethyl-pyridin- 3-chloro-2-methoxy- 414.7 4.60 2 3-yl phenyl 2-444-chloro-2,6- 3-chloro-2-methoxy- 450.7 5.84 2 dimethyl-pyridin-3-ylphenyl 2-45 6-methoxy-4-methyl- 3-chloro-2-methoxy- 430.7 8.07 2pyridin-3-yl phenyl 2-46 4-chloro-6-methyl- 3-chloro-2-methoxy- 434.76.94 2 pyridin-3-yl phenyl 2-47 2-chloro-6-methyl- 3-chloro-2-methoxy-434.7 8.00 2 pyridin-3-yl phenyl 2-48 3-formyl-quinolin-2-yl2-methoxy-phenyl 430.9 5.67 2 2-49 3-cyano-quinolin-2-yl2-methoxy-phenyl 427.9 5.63 2 2-50 5-methyl-thieno[2,3- 2-methoxy-phenyl423.7 7.07 2 d]pyrimidin-4-yl 2-51 4,6-di-trifluoromethyl-2-methoxy-phenyl 503.8 8.96 2 2-hydroxy-phenyl 2-522,4-di-trifluoromethyl- 2-methoxy-phenyl 487.8 9.75 2 phenyl 2-532-cyano-4- 2-methoxy-phenyl 444.8 6.16 2 trifluoromethyl-phenyl 2-542,4-dichloro-phenyl 2-methoxy-phenyl 419.8 6.54 2 2-55 4-chloro-2-cyano-2-methoxy-phenyl 410.8 6.04 2 phenyl 2-56 5-chloro-pyridin-2-yl2-methoxy-phenyl 387.0 9.38 3 2-57 5-chloro-3-methyl- 2-methoxy-phenyl400.8 7.83 2 pyridin-2-yl 2-58 3-chloro-5-methyl- 2-methoxy-phenyl 400.77.46 2 pyridin-2-yl 2-59 3,5-difluoro-pyridin-2- 2-methoxy-phenyl 388.87.39 2 yl 2-60 3,5-dimethyl-pyridin- 2-methoxy-phenyl 380.8 4.83 2 2-yl2-61 3-chloro-5- 2-methoxy-phenyl 454 8.65 2 trifluoromethyl-pyridin-2-yl 2-62 5-chloro-3-methyl- 2-fluoro-phenyl 388.8 7.94 2pyridin-2-yl 2-63 5-chloro-3-methyl- 2,6-dimethyl-phenyl 398.8 8.48 2pyridin-2-yl 2-64 3-chloro-5-methyl- 2,6-dimethyl-phenyl 398.8 8.07 2pyridin-2-yl 2-65 3-chloro-5- 2,6-dimethyl-phenyl 452.7 9.21 2trifluoromethyl- pyridin-2-yl 2-66 3,5-difluoro-pyridin-2-2,6-dimethyl-phenyl 386.8 8.02 2 yl 2-66 3,5-dimethyl-pyridin-2,6-dimethyl-phenyl 378.8 5.37 2 2-yl 2-67 3-chloro-5-methyl-2,3-dimethyl-phenyl 399.0 8.03 2 pyridin-2-yl 2-68 3,5-dimethyl-pyridin-2,3-dimethyl-phenyl 379.0 5.33 2 2-yl 2-69 3,5-dichloro-pyridin-2-methoxy-6-methyl- 436.9 10.08 2 2-yl phenyl 2-70 3,5-dimethyl-pyridin-3-chloro-2-methoxy- 414.7 5.38 2 2-yl phenyl 2-71 5-chloro-3-methyl-2,3-dimethyl-phenyl 398.7 8.48 2 pyridin-2-yl 2-72 5-chloro-3-methyl-2-benzoic acid methyl 428.7 7.58 2 pyridin-2-yl ester 2-733,5-difluoro-pyridin-2- 2-benzoic acid methyl 416.7 7.15 2 yl ester 2-743,5-dimethyl-pyridin- 2-benzoic acid methyl 408.8 4.71 2 2-yl ester 2-753-chloro-5- 2-benzoic acid methyl 482.7 8.38 2 trifluoromethyl- esterpyridin-2-yl 2-76 3-chloro-5- 2-fluoro-phenyl 442.9 8.64 2trifluoromethyl- pyridin-2-yl 2-77 3-chloro-5-methyl- 2-benzoic acidmethyl 428.7 7.21 2 pyridin-2-yl ester 2-78 3,5-dimethyl-pyridin-2-methoxy-6-methyl- 394.8 7.25 2 2-yl phenyl 2-79 3-methyl-quinolin-2-yl2-methoxy-phenyl 416.9 6.67 2 2-80 3,5-dichloro-6- 2-methoxy-phenyl 4358.63 2 methyl-pyridin-2-yl 2-81 4-cyano-6- 2-methylsulfanyl- 461.9 6.194 trifluoromethyl- phenyl pyridin-3-yl

Similarly, using 3-bromo-4-fluoro-benzoic acid as the starting material,3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-4-fluoro-N-(2-methoxy-phenyl)-N-methylbenzamide 2-82 was prepared. MS: 430.0 (M+H)⁺; t_(R)=5.73 min (method2).

Example 3(2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-aceticAcid Methyl Ester

Step 3A: 3-Bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-benzamide(Alternate Synthesis)

To 3-bromo-4-chloro-benzoyl chloride (Step 2A, 14.4 mmol) in DCM (70 mL)cooled with an ice bath, was added methoxy-N-methylaniline (2 g, 14.6mmol) in DCM (10 mL), followed by addition of diisopropylethylamine (3.4mL, 18.95 mmol) slowly. Upon completion of the addition, the ice bathwas removed and the mixture was stirred at room temperature for 48 hrs.The mixture was washed with 1 N HCl, saturated NaHCO₃, and brine, driedover Na₂SO₄, filtered and concentrated in vacuo to yield3-bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-benzamide as a solid (5.1g, 96%). MS [M+H]⁺: 355.7; t_(R)=2.89 min. (method 1)

Similarly, 9.2 g (88%)3-bromo-4-chloro-N-(2-methoxy-6-methyl-phenyl)-benzamide was preparedfrom 2-methoxy-6-methyl-phenylamine (4.2 g, 30.3 mmol). MS [M+H]⁺:355.9;t_(R)=2.80 min. (method 1)

Similarly, 2.35 g (93%) of3-bromo-4-chloro-N-(3-fluoro-2-methoxy-phenyl)-benzamide was preparedfrom 3-fluoro-2-methoxy-phenylamine (1 g, 7.08 mmol) with the differencethat silica gel column chromatography (eluent: EtOAc/hexanes=1/4) wasused for purification. MS[M+H]⁺: 359.9; t_(R)=2.56 min. (method 1)

Step 3A.1:3-Bromo-4-chloro-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide

This step was only used if the aniline used in step 3A was notN-methylated.

3-Bromo-4-chloro-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide (4.2g) was prepared from3-bromo-4-chloro-N-(2-methoxy-6-methyl-phenyl)-benzamide (4 g, 11.3mmol) using the procedure of Step 2C. MS [M+H]⁺:369.9; t_(R)=2.89 min.(method 1)

Similarly, 2.3 g (98%)3-bromo-4-chloro-N-(3-fluoro-2-methoxy-phenyl)-N-methyl-benzamide wasprepared from 3-bromo-4-chloro-N-(3-fluoro-2-methoxy-phenyl)-benzamide(2.3 g, 6.4 mmol). Silica gel column chromatography was used forpurification (eluent: EtOAc/hexanes=1/4 with gradient up to 2/3). MS[M+H]⁺:373.9; t_(R)=2.44 min. (method 1)

Step 3B: 3-Bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide

To a cooled solution (−70° C.) of3-bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-benzamide (2 g, 5.64mmol) in DCM (20 mL), BBr₃ (1.7 mL, 18 mmol) was added drop-wise over a20 minute period. The reaction temperature was allowed to increase toroom temperature over 12 hrs until completion of the reaction. Afterconcentration in vacuo the mixture was partitioned between DCM andwater. 1N NaOH was added to increase pH to ˜5. The organic layer wasseparated and washed with brine and dried over Na₂SO₄. Concentration andpurification by silica gel column chromatography eluting withhexane/ethyl acetate (4/1 with gradient up to 3/2) yielded3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (1.78 g, 93%).MS [M+H]⁺:341.9; t_(R)=2.56 min. (method 1)

Similarly 1.9 g (100%)3-bromo-4-chloro-N-(2-hydroxy-6-methyl-phenyl)-N-methyl-benzamide wasprepared from3-bromo-4-chloro-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide (2 g,5.4 mmol). MS [M+H]⁺:355.9; t_(R)=2.60 min. (method 1)

Similarly 1.65 g (90%) of3-bromo-4-chloro-N-(3-fluoro-2-hydroxy-phenyl)-N-methyl-benzamide wasprepared from3-bromo-4-chloro-N-(3-fluoro-2-methoxy-phenyl)-N-methyl-benzamide (1.9g, 5.1 mmol). MS [M+H]⁺:359.9; t_(R)=2.22 min. (method 1)

Step 3C: {2-[(3-Bromo-4-chloro-benzoyl)-methyl-amino]-phenoxy}-aceticAcid Methyl Ester

A mixture of 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide(442 mg, 1.3 mmol), methylbromoacetate (0.247 mL, 2.6 mmol) and K₂CO₃(717 mg, 5.2 mmol) was heated in DMF (8 mL) at 80° C. for 5 hrs. Aftercooling to room temperature, the mixture was partitioned between ethylacetate and water. The organic layer was separated and washed withbrine, dried over Na₂SO₄, then purified by silica gel columnchromatography eluted with ethyl acetate/hexane (1/4) to yield{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenoxy}-acetic acid methylester (495 mg). MS [M+H]⁺:413.9; t_(R)=2.75 min. (method 1)

4-{2-[(3-Bromo-4-chloro-benzoyl)-methyl-amino]-phenoxy}-butyric acidmethyl ester (0.41 g) was similarly prepared in 72% yield. MS[M+H]⁺:441.9; t_(R)=2.87 min. (method 1)

5-{2-[(3-Bromo-4-chloro-benzoyl)-methyl-amino]-phenoxy}-pentanoic acidmethyl ester (0.53 g) was similarly prepared in 99% yield. MS [M+H]⁺:456.0; t_(R)=2.94 min. (method 1)

4-{2-[(3-Bromo-4-chloro-benzoyl)-methyl-amino]-3-methyl-phenoxy}-butyricacid methyl ester (0.54 g) was similarly prepared in 85% yield. MS[M+H]⁺: 456.0; t_(R)=2.94 min. (method 1)

4-{2-[(3-Bromo-4-chloro-benzoyl)-methyl-amino]-6-fluoro-phenoxy}-butyricacid methyl ester (0.93 g) was similarly prepared in 93% yield. MS[M+H]⁺: 460.0; t_(R)=2.45 min. (method 1)

4-{2-[(3-Bromo-4-chloro-benzoyl)-methyl-amino]-3-methyl-phenoxy}-butyricacid tert-butyl ester (0.78 g) was similarly prepared in 79% yield. MS[M+H]⁺: 498.1; t_(R)=2.75 min. (method 1)

Step 3D:(2-{[4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenoxy)-aceticAcid Methyl Ester

A mixture of{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenoxy}-acetic acid methylester (495 mg, 1.2 mmol), bis(pinacolato)diboron (457 mg, 1.8 mmol),Pd(dppf)₂Cl₂ (70 mg, 2.4 mmol), potassium acetate (352 mg, 3.6 mmol) indioxane (10 mL) was degassed by bubbling N₂ for 5 minutes and then washeated under sealed condition to 95° C. for 14 hrs. Upon cooling to roomtemperature, the mixture was diluted with ethyl acetate, washed withwater and brine, and dried over Na₂SO₄. Concentration and purificationby silica gel column chromatography eluting with ethyl acetate/hexane(3/7) yielded(2-{[4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenoxy)-aceticacid methyl ester (0.61 g, 100% yield). MS [M+H]⁺:460.1; t_(R)=2.56 min(method 1)

Similarly, the following compounds were made from the corresponding arylbromides:

4-(2-{[4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricacid methyl ester (0.47 g, 100% yield) MS [M+H]+: 488; t_(R)=2.99 min(method 1)

4-(2-{[4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-butyricacid methyl ester (0.6 g, 100% yield) MS [M+H]⁺: 502.0; t_(R)=2.74 min(method 1)

4-(2-{[4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-6-fluoro-phenoxy)-butyricacid methyl ester (0.6 g, 100% yield) MS [M+H]⁺: 506.2; t_(R)=2.59 min(method 1)

4-(2-{[4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-butyricacid tert-butyl ester (0.39 g, 91% yield) MS [M+H]⁺: 544.2; t_(R)=2.81min (method 1).

Step 3D.1: Alternative Synthesis of4-(2-{[4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-butyricAcid Tert-Butyl Ester

2-Amino-m-cresol (4.9 g, 40 mmol) was dissolved in a mixture ofacetonitrile (90 mL) and water (80 mL) containing NaHCO₃ (6.7 g, 80mmol) with vigorous stirring. 3-Bromo-4-chloro-benzoyl chloride (10.1 g,40 mmol, Step 2A) was added in several portions and the mixture wasstirred at room temperature for 3 hrs. The resulting precipitates werefiltered, washed with water and tert-butyl methyl ether, then dried toyield 3-bromo-4-chloro-N-(2-hydroxy-6-methyl-phenyl)-benzamide (11.3 g).MS (M+H)⁺: 339.7/341.7; t_(R)=2.36 min. (method 1)

A mixture of 3-bromo-4-chloro-N-(2-hydroxy-6-methyl-phenyl)-benzamide(11.3 g, 33.2 mmol), t-butyl 4-bromobutyrate (8.2 g, 36.6 mmol) andK₂CO₃ (9.2 g, 66.5 mmol) was heated in DMF (100 mL) at 60° C. for 14hrs. The mixture was then concentrated to remove DMF and partitionedbetween ethyl acetate and water. The organic layer was separated andwashed with water and brine, dried over MgSO₄, then purified by silicagel column chromatography eluting with ethyl acetate/hexane (1/4) toyield a red solid, which was further washed with ether to produce awhite powder as4-[2-(3-bromo-4-chloro-benzoylamino)-3-methyl-phenoxy]-butyric acidtert-butyl ester (10.2 g). MS [M-(t-Bu)+H]⁺:425.8/427.8; t_(R)=2.79 min.(method 1)

To a solution of4-[2-(3-bromo-4-chloro-benzoylamino)-3-methyl-phenoxy]-butyric acidtert-butyl ester (10.2 g, 21.3 mmol) in dry DMF (100 mL) at 0° C. underN₂, NaH (60% in mineral oil, 1.7 g, 42.6 mmol) was added in severalportions with stirring. 10 minutes later, iodomethane (2.0 mL, 32.1mmol) was added. The mixture was warmed to room temperature by removalof ice bath and stirring was continued for 1 hr. Water (10 mL) was thenadded and organics were extracted by ethyl acetate, which was thenwashed by water and brine, and was dried over MgSO₄. Afterconcentration, the crude product was purified by silica gelchromatography eluting with ethyl acetate/hexane (1/4) to yield4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-3-methyl-phenoxy}-butyricacid tert-butyl ester (9.5 g).

A mixture of4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-3-methyl-phenoxy}-butyricacid tert-butyl ester (6.1 g, 12.3 mmol), bis(pinacolato)diboron (4.7 g,18.5 mmol), Pd(dppf)₂Cl₂ (0.73 g, 1.0 mmol) and potassium acetate (3.6g, 36.9 mmol) in dioxane (80 mL) was degassed by bubbling N₂ for 5minutes and then heated under sealed condition to 95° C. for 14 hrs.Upon cooling to room temperature, the mixture was passed through a padof Celite. The Celite was further washed with ethyl acetate. Thecombined solutions were washed with water and brine, and were dried overMgSO₄. Concentration and purification by silica gel columnchromatography eluting with ethyl acetate/hexane (1/4) yielded4-(2-{[4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-butyricacid tert-butyl ester (6.5 g) as a light yellow oil.

4-(2-{[4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricacid tert-butyl ester was prepared similarly. MS [M+H-iso-butene]⁺:474.2; t_(R)=2.72 min. (method 1)

Step 3E:(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-aceticAcid Methyl Ester

A mixture of(2-{[4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenoxy)-aceticacid methyl ester (45 mg, 0.11 mmol), 5-bromo-2-chloro-4-methyl-pyridine(25 mg, 0.12 mmol), Pd(PPh₃)₄ (6.5 mg, 0.0056 mmol), and K₂CO₃ (38 mg,0.28 mmol) in dioxane (600 ul), was heated at 95° C. for 12 hrs. Themixture was purified after a filtration by prep. LCMS to yield(2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-aceticacid methyl ester 3-1. MS [M+H]⁺:459.0; t_(R)=7.70 min; (method 2)

The following compounds were prepared according to the proceduresdescribed above.

Ex. A

MS ion t_(R) (min) HPLC Method 3-1 6-chloro-4-methyl-2-[(methoxycarbonyl)- 459.0 7.70 2 pyridin-3-yl methoxy]-phenyl 3-26-chloro-4-methyl- 2-[3-(methoxycarbonyl)- 487.0 8.21 2 pyridin-3-ylpropyloxy]-phenyl 3-3 6-cyano-4-methyl- 2-[(methoxycarbonyl)- 450.0 7.32 pyridin-3-yl methoxy]-phenyl 3-4 4-chloro-6-methyl-2-[(methoxycarbonyl)- 459.0 6.13 2 pyridin-3-yl methoxy]-phenyl 3-56-chloro-4-methyl- 2-[3-(methoxycarbonyl)- 500.9 8.80 2 pyridin-3-ylpropyloxy]-6-methyl- phenyl 3-6 6-chloro-4-methyl- 3-fluoro-2-[3- 504.98.60 2 pyridin-3-yl (methoxycarbonyl)- propyloxy]-phenyl 3-7 4-methyl-6-2-[3-(methoxycarbonyl)- 521.3 8.89 2 trifluoromethyl- propyloxy]-phenylpyridin-3-yl 3-8 6-cyano-4-methyl- 2-[3-(methoxycarbonyl)- 478.1 7.76 2pyridin-3-yl propyloxy]-phenyl 3-9 6-cyano-4-methyl-2-[3-(methoxycarbonyl)- 491.9 8.38 2 pyridin-3-yl propyloxy]-6-methyl-phenyl 3-10 4-cyano-6- 2-[3-(methoxycarbonyl)- 531.8 8.88 2trifluoromethyl- propyloxy]-phenyl pyridin-3-yl 3-11 4-cyano-6-2-[3-(methoxycarbonyl)- 545.8 9.09 2 trifluoromethyl-propyloxy]-6-methyl- pyridin-3-yl phenyl 3-12 4-cyano-6- 3-fluoro-2-[3-549.9 8.92 2 trifluoromethyl- (methoxycarbonyl)- pyridin-3-ylpropyloxy]-phenyl 3-13 4-methyl-6- 3-fluoro-2-[3- 539.3 9.08 2trifluoromethyl- (methoxycarbonyl)- pyridin-3-yl propyloxy]-phenyl 3-144-methyl-6- 3-fluoro-2-[3- 504.9 8.60 2 trifluoromethyl-(methoxycarbonyl)- pyridin-3-yl propyloxy]-phenyl 3-15 6-cyano-4-methyl-3-fluoro-2-[3- 495.9 8.21 2 pyridin-3-yl (methoxycarbonyl)-propyloxy]-phenyl 3-16 4-methyl-6- 2-[3-(t-butyloxycarbonyl)- 577.210.54 2 trifluoromethyl- propyloxy]-phenyl pyridin-3-yl 3-17 3-chloro-5-2-[3-(t-butyloxycarbonyl)- 596.9 10.68 2 trifluoromethyl-propyloxy]-phenyl pyridin-2-yl 3-18 3-cyano-quinolin-2-2-[3-(t-butyloxycarbonyl)- 569.9 2.77 1 yl propyloxy]-phenyl 3-193-cyano-quinolin-2- 2-[3-(t-butyloxycarbonyl)- 499.7 10.61 2 ylpropyloxy]-phenyl 3-20 4-cyano-2-methyl- 2-[3-(t-butyloxycarbonyl)-519.8 2.63 1 phenyl propyloxy]-phenyl 3-21 4-cyano-6-2-[3-(t-butyloxycarbonyl)- 517.9 2.89 1 trifluoromethyl-propyloxy]-phenyl pyridin-3-yl 3-22 4-cyano-6-2-[3-(t-butyloxycarbonyl)- 531.8 10.35 2 trifluoromethyl-propyloxy]-6-methyl- pyridin-3-yl phenyl 3-23 4-chloro-2-cyano-2-[3-(t-butyloxycarbonyl)- 482.9 6.63 4 phenyl propyloxy]-phenyl

Example 4(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-aceticAcid

Step 4A:(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-aceticAcid

(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-aceticacid methyl ester (10 mg, 0.02 mmol) was dissolved in THF (300 μL) and1M LiOH (100 μL) was added. The mixture was stirred at room temperatureuntil LCMS indicated that starting material was completely consumed. Themixture was diluted with EtOAc and acidified with 1N HCl. The organiclayer was concentrated, dissolved in MeOH and purified by prep LCMS toyield(2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-aceticacid 4-1. MS [M+H]⁺: 445.0; t_(R)=6.75 min, (method 2)

The following compounds were prepared according to the proceduredescribed above. In cases where the molecule was substituted with acyano group it should be noted that lithium hydroxide was added in 3portions over a 90 minute period. Typically at 0.04 mmole of startingester in 200 μL THF, a 1N solution of LiOH (60 μL) was added in 3×20 μLportions every 30 minutes. The reaction was allowed to proceed for 4hours.

Ex. A

MS (M + H)⁺ t_(R) (min) HPLC method 4-1 6-chloro-4-methyl-2-[(hydroxycarbonyl)- 445.0 6.75 2 pyridin-3-yl methoxy]-phenyl 4-26-chloro-4-methyl- 2-[3-(hydroxycarbonyl)- 473.0 7.17 2 pyridin-3-ylpropyloxy]-phenyl 4-3 6-chloro-4-methyl- 2-[3-(hydroxycarbonyl)- 486.87.71 2 pyridin-3-yl propyloxy]-6-methyl- phenyl 4-4 6-chloro-4-methyl-3-fluoro-2-[3- 490.8 7.49 2 pyridin-3-yl (hydroxycarbonyl)-propyloxy]-phenyl 4-5 6-chloro-4-methyl- 2-[4-(hydroxycarbonyl)- 487.07.42 2 pyridin-3-yl butyloxy]-phenyl 4-6 4-methyl-6-2-[3-(hydroxycarbonyl)- 507.1 4.82 2 trifluoromethyl- propyloxy]-phenylpyridin-3-yl 4-7 4-methyl-6- 3-fluoro-2-[3- 525.1 3.77 2trifluoromethyl- (hydroxycarbonyl)- pyridin-3-yl propyloxy]-phenyl 4-86-cyano-4-methyl- 2-[3-(hydroxycarbonyl)- 477.9 7.35 2 pyridin-3-ylpropyloxy]-6-methyl- phenyl 4-9 6-cyano-4-methyl- 3-fluoro-2-[3- 481.97.12 2 pyridin-3-yl (hydroxycarbonyl)- propyloxy]-phenyl 4-10 4-cyano-6-2-[3-(hydroxycarbonyl)- 517.8 7.84 2 trifluoromethyl- propyloxy]-phenylpyridin-3-yl 4-11 4-cyano-6- 2-[3-(hydroxycarbonyl)- 531.8 8.15 2trifluoromethyl- propyloxy]-6-methyl- pyridin-3-yl phenyl 4-124-cyano-6- 3-fluoro-2-[3- 535.8 7.88 2 trifluoromethyl-(hydroxycarbonyl)- pyridin-3-yl propyloxy]-phenyl

Example 54-(2-{[4-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricAcid

Step 5A:4-(2-{[4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricAcid

4-(2-{[4-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricacid tert-butyl ester (60 mg, 0.12 mmol) was stirred in a mixture of DCM(400 μL) and TFA (400 μL) for 1 hr. The mixture was concentrated,dissolved in MeOH and purified by prep LCMS to yield4-(2-{[4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricacid 5-1. MS [M+H]⁺: 463.7; t_(R)=3.46 min, (method 2)

The following compounds were prepared according to the proceduredescribed above.

Ex. A

MS (M + H)⁺ t_(R) (min) Method 5-1 6-cyano-4-methyl-2-[3-(hydroxycarbonyl)- 463.7 3.46 2 pyridin-3-yl propyloxy]-phenyl 5-24-methyl-6- 2-[3-(hydroxycarbonyl)- 521.2 8.13 2 trifluoromethyl-propyloxy]-6-methyl- pyridin-3-yl phenyl 5-3 3-chloro-5-2-[3-(hydroxycarbonyl)- 540.8 8.17 2 trifluoromethyl-propyloxy]-6-methyl- pyridin-2-yl phenyl 5-4 3-cyano-quinolin-2-2-[3-(hydroxycarbonyl)- 513.8 4.78 2 yl propyloxy]-6-methyl- phenyl 5-53-cyano-quinolin-2- 2-[3-(hydroxycarbonyl)- 500.2 24.60 5 ylpropyloxy]-phenyl 5-6 4-chloro-2-cyano- 2-[3-(hydroxycarbonyl)- 482.87.81 2 phenyl propyloxy]-phenyl

Example 6N-(2-Carbamoylmethoxy-phenyl)-4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-methyl-benzamide

Step 6A:N-(2-Carbamoylmethoxy-phenyl)-4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-methyl-benzamide

(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-aceticacid methyl ester (28 mg, 0.06 mmol) was dissolved in 7N ammonia in MeOH(1 mL) and stirred at room temperature until starting material wasconsumed. The mixture was concentrated and taken up in MeOH, filteredand washed with methanol to yieldN-(2-carbamoylmethoxy-phenyl)-4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-methyl-benzamide6-1. MS [M+H]⁺: 444.0; t_(R)=6.25 min; (method 2)

Similarly,N-[2-(3-carbamoyl-propoxy)-phenyl]-4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-methyl-benzamide6-2, MS [M+H]⁺: 472.0 t_(R)=6.51 min; (method 2) and

N-[2-(4-carbamoyl-butoxy)-phenyl]-4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-methyl-benzamide6-3, MS [M+H]⁺: 485.9; t_(R)=6.87 min; (method 2) were prepared.

Example 74-Chloro-3-(4,6-dichloro-pyridin-3-yl)-N-[2-(2-dimethylamino-ethoxy)-phenyl]-N-methyl-benzamide

Step 7A:3-Bromo-4-chloro-N-[2-(2-dimethylamino-ethoxy)-phenyl]-N-methyl-benzamide

A mixture of 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide(404 mg, 1.18 mmol, Step 3B), β-dimethylaminobromide hydrobromide (553mg, 2.38 mmol) and K₂CO₃ (655 mg, 4.75 mmol) was heated in DMF (7 mL) at80° C. for 14 hrs. The mixture was then diluted with ethyl acetate andwater. The organic layer was separated and washed with water and brine,dried over Na₂SO₄, then purified by silica gel column chromatographyeluting with DCM/MeOH (95/5 with gradient to 9/1) to yield3-bromo-4-chloro-N-[2-(2-dimethylamino-ethoxy)-phenyl]-N-methyl-benzamide(97 mg). MS [M+H]⁺: 412.7; t_(R)=2.24 min. (method 1)

Step 7B:4-Chloro-3-(4,6-dichloro-pyridin-3-yl)-N-[2-(2-dimethylamino-ethoxy)-phenyl]-N-methylBenzamide

A mixture of dioxane (1.0 mL) containing3-bromo-4-chloro-N-[2-(2-dimethylamino-ethoxy)-phenyl]-N-methyl-benzamide(44.0 mg, 0.11 mmol), Pd₂(dba)₃ (10 mg, 0.01 mmol), P(t-Bu)₃HBF₄ (7 mg,0.022 mmol), KF (22 mg, 0.38 mmol) and 2,4 dichloropyridine-5-boronicacid (21 mg, 0.11 mmol) was degassed by bubbling N₂ for 5 minutes andthen sealed and heated at 110° C. overnight. The mixture was filteredand purified by preparative LCMS to yield4-chloro-3-(4,6-dichloro-pyridin-3-yl)-N-[2-(2-dimethylamino-ethoxy)-phenyl]-N-methylbenzamide 7-1. MS [M+H]⁺: 478.0; t_(R)=5.26 min. (method 2)

Example 84-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide

Step 8A:4-Chloro-N-(2-hydroxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide

A mixture of 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide(485 mg, 1.42 mmol, Step 3B), bis(pinacolato)diboron (0.543 g, 2.1mmol), Pd(dppf)₂Cl₂ (83 mg, 0.11 mmol) and potassium acetate (419 mg,4.3 mmol) in dioxane (10 mL) was degassed by bubbling N₂ for 5 minutesand then heated under sealed condition to 95° C. for 14 hrs. Uponcooling to room temperature, the mixture was diluted with ethyl acetateand washed with water and brine, then dried over Na₂SO₄. Concentrationfollowed by purification by silica gel column chromatography elutingwith ethyl acetate/hexane (1/4 up to 2/3) gave4-chloro-N-(2-hydroxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(540 mg). MS [M+H]⁺: 388.1; t_(R)=2.74 min. (method 1)

Step 8B:4-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide

A mixture of4-chloro-N-(2-hydroxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(100 mg, 0.26 mmol), 5-bromo-4-methyl-pyridine-2-carbonitrile (61 mg,0.31 mmol), Pd(PPh₃)₄ (15 mg, 0.013 mmol), K₂CO₃ (90 mg, 0.65 mmol) indioxane (1.2 mL), was heated at 95° C. for 12 hrs. The mixture wasdiluted with EtOAc, washed with water and brine, dried (Na₂SO₄) andconcentrated in vacuo. Silica gel column chromatography (eluent: ethylacetate/hexane (1/4 up to 4/1)) yielded4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide8-1 (68 mg).

The following compounds were prepared according to the proceduredescribed above.

Ex. A

MS (M + H)⁺ t_(R) (min) method 1 8-1 6-cyano-4-methyl- 2-hydroxy-phenyl378.1 2.22 pyridin-3-yl 8-2 6-chloro-4-methyl- 2-hydroxy-phenyl 387.02.27 pyridin-3-yl 8-3 4-methyl-6- 2-hydroxy-phenyl 421.0 2.36trifluoromethyl- pyridin-3-yl 8-4 4-cyano-6- 2-hydroxy-phenyl 432.0 2.32trifluoromethyl- pyridin-3-yl 8-5 6-cyano-4-methyl- 2-hydroxy-6-methyl-392.1 2.25 pyridin-3-yl phenyl 8-6 4-methyl-6- 2-hydroxy-6-methyl- 435.12.41 trifluoromethyl- phenyl pyridin-3-yl 8-7 4-cyano-6-2-hydroxy-6-methyl- 446.1 2.33 trifluoromethyl- phenyl pyridin-3-yl

Example 94-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-[2-(3-hydroxy-propoxy)-phenyl]-N-methyl-benzamide

Step 9A:4-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-[2-(3-hydroxy-propoxy)-phenyl]-N-methyl-benzamide

A mixture of4-chloro(6-cyano-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide8-1 (50 mg, 0.13 mmol), 4-bromopropanol (18 μL, 0.2 mmol) and K₂CO₃ (55mg, 0.40 mmol) in DMF (0.4 mL) was stirred at room temperature for 14hrs. Ethyl acetate was added and the combined organic layers were washedwith water, dried over Na₂SO₄, then purified by silica gel columnchromatography eluting with ethyl acetate/hexane (2/3) up to 100% EtOActo yield4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-[2-(3-hydroxy-propoxy)-phenyl]-N-methyl-benzamide(30 mg). Example 1. MS [M+H]⁺: 436.1; t_(R)=2.19 min. (method 1)

The following compounds were prepared according to the proceduredescribed above.

Ex. A

MS (M + H)⁺ t_(R) (min) HPLC Method 9-1 6-cyano-4- 2-(3-hydroxy- 436.12.18 1 methyl- propoxy)-phenyl pyridin-3-yl 9-2 6-chloro-4-2-(3-hydroxy- 445.1 2.26 1 methyl- propoxy)-phenyl pyridin-3-yl 9-34-methyl-6- 2-(3-hydroxy- 479.1 2.33 1 trifluoromethyl- propoxy)-phenylpyridin-3-yl 9-4 4-cyano-6- 2-(3-hydroxy- 490.1 2.30 1 trifluoromethyl-propoxy)-phenyl pyridin-3-yl 9-5 6-cyano-4- 2-(3-hydroxy- 449.9 7.00 2methyl- propoxy)-6-methyl- pyridin-3-yl phenyl 9-6 4-methyl-6-2-(3-hydroxy- 492.1 2.40 1 trifluoromethyl- propoxy)-6-methyl-pyridin-3-yl phenyl 9-7 4-cyano-6- 2-(3-hydroxy- 504.1 2.34 1trifluoromethyl- propoxy)-6-methyl- pyridin-3-yl phenyl

Example 104-Chloro-3-(2-cyano-4-trifluoromethyl-phenyl)-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-benzamide

Step 10A:3-Bromo-4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-benzamide

3-Bromo-1-propanol (2.48 mL, 27.3 mmol) was added to a solution of3-bromo-4-chloro-N-(2-hydroxy-6-methyl-phenyl)-N-methyl-benzamide (6.47g, 18.3 mmol, Step 3B) in DMF (80 mL). To this was added K₂CO₃ (3.3 g,24 mmol) and the mixture was stirred at room temperature forapproximately 16 hrs. At this time the reaction was neutralized with 1Nhydrochloric acid and the mixture was extracted with ethyl acetate. Theorganic layer was washed with first water and then brine solution. Theorganic filtrate was evaporated and the residue purified using columnchromatography in a gradient of 50% ethyl acetate to 60% ethyl acetatein hexanes giving3-bromo-4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-benzamide(5.7 g, 76%). MS [M+H]⁺: 413.9; t_(R)=2.29 min. (method 1)

Similarly,3-bromo-4-chloro-N-[2-(3-hydroxy-propoxy)-phenyl]-N-methyl-benzamide wasprepared from the corresponding3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (Step 3B). MS[M+H]⁺: 399.6; t_(R)=2.21 min. (method 1)

Step 10B:4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide

A mixture of3-bromo-4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-benzamide(5.5 g, 13.4 mmol), bis(pinnacolato)diboron (5.1 g, 20.0 mmol),PdCl₂(dppf)₂ (781.7 mg, 1.1 mmol) and KOAc (3.92 g, 40.1 mmol) indioxane (70 mL), was heated at 95° C. for approximately 16 hrs afterdegassing of the solvent with a stream of nitrogen. The mixture wasallowed to cool to room temperature and then filtered over a celite pad.The pad was further washed with EtOAc. The combined organics were washedwith water and brine and dried with MgSO₄. The filtrate from this wasconcentrated in vacuo and the residue purified by silica gel columnchromatography (eluent: 20% ethyl acetate in hexane) to afford4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(5.5 g). MS [M+H]⁺: 460.1; t_(R)=2.47 min. (method 1)

Similarly,4-chloro-N-[2-(3-hydroxy-propoxy)-phenyl]-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamidewas prepared. MS [M+H]⁺: 446.0; t_(R)=2.42 min. (method 1)

Step 10C:4-chloro-3-(2-cyano-4-trifluoromethyl-phenyl)-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-benzamide

A mixture of4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(206 mg, 0.45 mmol), 2-bromo-5-(trifluoromethyl)-benzonitrile (75 mg,0.3 mmol), Pd(PPh₃)₄ (34.7 mg, 0.03 mmol), Na₂CO₃ (190.8 mg, 1.8 mmol)in dioxane/water (9/1, 1.5 mL), was heated at 95° C. for approximately16 hrs after degassing of the solvent with a stream of nitrogen. Thereaction was allowed to cool to room temperature. The mixture wasdiluted with water and extracted with ethyl acetate. The organic layerwas further washed with brine and dried with MgSO₄. The filtrate wasevaporated and the residue purified by preparative TLC [eluent: 40%acetone in hexane] to afford4-chloro-3-(2-cyano-4-trifluoromethyl-phenyl)-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-benzamide10-1 (120 mg). MS [M+H]⁺: 502.9; t_(R)=8.15 min. (method 2)

Similarly,4-chloro-3-(3-cyano-quinolin-2-yl)-N-[2-(3-hydroxy-propoxy)-phenyl]-N-methyl-benzamide10-2 was prepared. MS [M+H]⁺: 471.9; t_(R)=6.89 min. (method 2)

Example 113-(2-{[4-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicAcid

Step 11 A:3-(2-{[4-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicAcid

To a mixture of4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-[2-(3-hydroxy-propoxy)-phenyl]-N-methyl-benzamide9-1 (30 mg, 0.07 mmol) in acetonitrile (0.25 mL) and dichloromethane(0.25 mL), a solution of sodium periodate (40 mg, 0.19 mmol) in water(0.4 mL) was added followed by ruthenium (III) chloride (2 mg, 0.0096mmol). The mixture was stirred 15 min, diluted with MeOH, stirred for 15min and filtered. The filtrate was purified by prep. LCMS to yield3-(2-{[4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicacid 11-1. MS [M+H]⁺: 449.8; t_(R)=6.76 min. (method 2)

The following compounds were prepared according to the proceduredescribed above.

Ex. A

MS (M + H)⁺ t_(R) (min) method 2 11-1 6-cyano-4-methyl-2-[2-(hydroxycarbonyl)- 449.8 6.76 pyridin-3-yl ethoxy]-phenyl 11-26-chloro-4-methyl- 2-[2-(hydroxycarbonyl)- 458.8 7.13 pyridin-3-ylethoxy]-phenyl 11-3 4-methyl-6- 2-[2-(hydroxycarbonyl)- 492.9 7.60trifluoromethyl-pyridin- ethoxy]-phenyl 3-yl 11-4 4-cyano-6-2-[2-(hydroxycarbonyl)- 503.8 7.62 trifluoromethyl-pyridin-2-ethoxy]-phenyl 3-yl 11-5 4-methyl-6- 2-[2-(hydroxycarbonyl)- 506.9 7.88trifluoromethyl-pyridin- ethoxy]-6-methyl-phenyl 3-yl 11-66-cyano-4-methyl- 2-[2-(hydroxycarbonyl)- 463.9 7.04 pyridin-3-ylethoxy]-6-methyl-phenyl 11-7 4-cyano-6- 2-[2-(hydroxycarbonyl)- 517.87.85 trifluoromethyl-pyridin- ethoxy]-6-methyl-phenyl 3-yl 11-82-cyano-4- 2-[2-(hydroxycarbonyl)- 516.8 8.17 trifluoromethyl-phenylethoxy]-6-methyl-phenyl 11-9 3-cyano-quinolin-2-yl2-[2-(hydroxycarbonyl)- 485.9 6.96 ethoxy]-phenyl

Example 125-(2-{[4-Chloro-3-(6-chlor-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-pentanoicAcid Methyl Ester

Step 12A:4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide

A mixture of4-chloro-N-(2-hydroxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(100 mg, 0.26 mmol, Step 8A), 5-bromo-2-chloro-4-methyl-pyridine (200mg, 0.52 mmol), Pd(PPh₃)₄ (30 mg, 0.026 mmol), K₂CO₃ (180 mg, 1.3 mmol)in dioxane (2.5 mL), was heated at 100° C. for 12 hrs. The mixture wasdried in vacuo in the presence of silica gel and directlychromatographed on silica gel (eluent: ethyl acetate/hexane (1/4 up to2/3)) to yield4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide(120 mg). MS [M+H]⁺: 387.0; t_(R)=2.27 min. (method 1)

Step 12B:5-(2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-pentanoicAcid Methyl Ester

A mixture of4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide(108 mg, 0.28 mmol), bromo methylvalerate (60 μL, 0.42 mmol) and K₂CO₃(116 mg, 0.84 mmol) in DMF (1 mL) was stirred at room temperature for 14hrs. Ethyl acetate was added and the combined organic layers were washedwith water, dried over MgSO₄, then purified by silica gel columnchromatography eluted with ethyl acetate/hexane (1/4) up to 1/3 to yield5-(2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-pentanoicacid methyl ester 12-1 (50 mg). MS [M+H]⁺: 501; t_(R)=8.52 min. (method1)

Example 134-(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenyl)-butyricAcid Methyl Ester

Step 13A: 1,3,4,5-tetrahydrobenzo[b]azepin-2-one

To a solution of α-tetralone (10 g, 68.5 mmol) in anhydrous MeOH (175mL), hydroxylamine hydrochloride (7.6 g, 109.6 mmol) and triethylamine(15.3 mL, 109.6 mmol) were added. The mixture was stirred at roomtemperature for 16 hrs, followed by removal of the solvent in vacuo. Theresidue was dissolved in DCM, washed with water and brine, dried(Na₂SO₄), filtered and concentrated in vacuo to yield crude3,4-dihydro-2H-naphthalen-1-one oxime (12 g). MS [M+H]⁺: 162.1;t_(R)=2.03 min. (method 1)

To 3,4-dihydro-2H-naphthalen-1-one oxime (5 g, 31 mmol), PPA (50 g) wasadded and the mixture was heated at 120° C. for 4.5 hrs. While hot themixture was quenced in a slurry of ice and water and vigorously stirreduntil a precipitate formed. The precipitate was filtered and rinsed withwater to yield 1,3,4,5-tetrahydrobenzo[b]azepin-2-one (3.1 g). MS[M+H]⁺: 162.0; t_(R)=1.76 min. (method 1)

Step 13B: 4-(2-Amino-phenyl)-butyric Acid Methyl Ester

To 1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1 g, 6.2 mmol) in MeOH (8mL), concentrated sulfuric acid (0.5 mL) was added and the mixture wasstirred at room temperature for 2 hrs and at 70° C. for an additionalhr. The solvent was removed and DCM and water were added. The organiclayer was removed and the aqueous layer was basified with sat NaHCO₃ andextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to yield4-(2-amino-phenyl)-butyric acid methyl ester (0.93 g). MS [M+H]⁺: 194.1;t_(R)=1.49 min. (method 1)

Step 13C: 4-[2-(3-bromo-4-chloro-benzoylamino)-phenyl]-butyric AcidMethyl Ester

To 3-bromo-4-chloro-benzoyl chloride (1.09 g, 4.3 mmol) in DCM (30 mL)cooled with an ice bath, was added 4-(2-amino-phenyl)-butyric acidmethyl ester (0.85 g, 4.4 mmol), followed by addition ofdiisopropylethylamine (1 mL, 5.6 mmol) slowly. Upon the completion ofthe addition, ice bath was removed and the mixture was stirred at roomtemperature for 12 hrs. The mixture was further diluted with DCM, washedwith saturated NaHCO₃, 1N HCl, brine and dried over Na₂SO₄ andconcentrated to yield4-[2-(3-bromo-4-chloro-benzoylamino)-phenyl]-butyric acid methyl ester(1.8 g). MS [M+H]⁺: 411.7; t_(R)=2.45 min. (method 1)

Step 13D: 4-{2-[(3-Bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyricAcid Methyl Ester

To 4-[2-(3-bromo-4-chloro-benzoylamino)-phenyl]-butyric acid methylester (1.04 g, 2.54 mmol) in DMF (10 mL) at 0-5° C., was added NaH (152mg, 3.81 mmol, 60% in mineral oil) in two portions. The mixture wasstirred for 15 min at 0° C. and 15 min at rt. After addition ofiodomethane (316 μl, 5.08 mmol), the mixture was stirred at roomtemperature for 12 hrs and was partitioned between ethyl acetate andcitric acid. The separated organic layer was then washed with brine anddried over Na₂SO₄. Concentration and purification by silica gel columnchromatography eluting with hexane/ethyl acetate (4/1) up tohexane/ethyl acetate (3/2) yielded4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acidmethyl ester (1.0 g). MS [M+H]⁺: 426.0; t_(R)=2.46 min. (method 1)

Step 13E:4-(2-{[4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyricAcid Methyl Ester

A mixture of4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acidmethyl ester (500 mg, 1.18 mmol), bis(pinacolato)diboron (448 mg, 1.76mmol), Pd(dppf)₂Cl₂ (69 mg, 0.094 mmol) and potassium acetate (347 mg,3.54 mmol) in dioxane (10 mL) was degassed by bubbling N₂ for 5 minutesand then heated under sealed condition to 95° C. for 14 hrs. Uponcooling to room temperature, the mixture was diluted with ethyl acetateand washed with water and brine, then dried over Na₂SO₄. Concentrationand purification by silica gel column chromatography eluting with ethylacetate/hexane (1/4 up to 2/3) gave4-(2-{[4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyricacid methyl ester as an oil (601 mg). MS [M+H]⁺: 472.2; t_(R)=2.57 min.(method 1)

Step 13F:4-(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenyl)-butyricAcid Methyl Ester

A mixture of4-(2-{[4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyricacid methyl ester (50 mg, 0.11 mmol), 5-bromo-2-chloro-pyridine (26 mg,0.13 mmol), Pd(PPh₃)₄ (6 mg, 0.005 mmol), K₂CO₃ (36 mg, 0.18 mmol) indioxane (0.6 mL), was heated at 100° C. for 12 hrs. The mixture waspurified after a filtration by prep. LCMS to yield4-(2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenyl)-butyricacid methyl ester 13-1. MS [M+H]⁺: 470.9; t_(R)=8.41 min. (method 2).

The following compounds were prepared according to the proceduredescribed above.

MS t_(R) Ex. A (M + H)⁺ (min) HPLC Method 13-16-chloro-4-methyl-pyridin-3-yl 470.9 8.41 2 13-26-cyano-4-methyl-pyridin-3-yl 461.9 7.95 2 13-34-cyano-6-trifluoromethyl- 516.2 8.86 2 pyridin-3-yl 13-44-methyl-6-trifluoromethyl- 504.9 8.92 2 pyridin-3-yl

Example 144-(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenyl)-butyricAcid

Step 14A:4-(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenyl)-butyricAcid

4-(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenyl)-butyricacid methyl ester 13-1 (9 mg, 0.019 mmol) was dissolved in THF (0.2 mL)and 1M LiOH (0.15 mL) was added. After 1 hour extra 1N LiOH (0.15 mL)was added and the mixture was stirred at room temperature until LCMSindicated that starting material was completely consumed. The mixturewas acidified with 1N HCl until pH˜5, MeOH was added and purified byprep LCMS to yield4-(2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenyl)-butyricacid 14-1. MS [M+H]⁺: 456.9; t_(R)=7.33 min. (method 2)

The following compounds were prepared according to the proceduredescribed above.

MS t_(R) HPLC Ex. A (M + H)⁺ (min) Method 14-16-chloro-4-methyl-pyridin-3-yl 456.9 7.33 2 14-24-methyl-6-trifluoromethyl-pyridin- 491.1 7.82 2 3-yl 14-36-cyano-4-methyl-pyridin-3-yl 448.2 6.97 2 14-44-cyano-6-trifluoromethyl-pyridin- 502.1 7.77 2 3-yl

Example 154-(2-{[4-Chloro-3-(3-cyano-quinolin-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyricAcid

Step 15A: 4-{2-[(3-Bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyricAcid

To a solution of4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acidmethyl ester (1.11 g, 2.6 mmol, Step 13D) in THF (8 mL), 2N LiOH (6.5mL) was added and the mixture was stirred for 2 hours at rt. 1N HCl wasadded to the reaction mixture to yield a pH˜2 followed by extractionwith EtOAc (2×). The combined organic layers were washed with water andbrine, dried (Na₂SO₄) and concentrated in vacuo to afford 1.1 g of4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid as awhite solid. MS [M+H]⁺:411.7; t_(R)=2.57 min, (method 1)

Step 15B: 4-{2-(3-Bromo-4-chloro-benzoyl)-methyl-aminol-phenyl}-butyricAcid Tert-Butyl Ester

To a cooled solution (0° C.) of4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid(1.07 g, 2.60 mmol) in anhydrous DCM (10 mL), oxalyl chloride (0.34 mL,3.90 mmol) was added dropwise. The mixture was stirred at roomtemperature for 4 hours, concentrated in vacuo and redissolved inanhydrous dichloromethane (5 mL). A solution of t-butanol (960 mg, 13mmol) in anhydrous DCM (5 mL) was added and the mixture was stirred atroom temperature overnight. After dilution with DCM, the mixture waswashed with sat NaHCO₃ and brine, dried over Na₂SO₄, filtered andconcentrated. Purification by silica gel column chromatography(EtOAc/Hexanes: 1/4 with gradient up to EtOAc/Hexanes 1/3) afforded 1.1g of 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acidtert-butyl ester as a colorless oil. MS [M+H]⁺ (fragment): 411.7 (f;t_(R)=3.10 min, (method 1)

Step 15C:4-(2-{[4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyricAcid Tert-Butyl Ester

A mixture of4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acidtert-butyl ester (1.0 g, 2.14 mmol), bis(pinacolato)diboron (816 mg,3.21 mmol), Pd(dppf)₂Cl₂ (125 mg, 0.1117 mmol) and potassium acetate(629 mg, 6.42 mmol) in dioxane (20 mL) was degassed by bubbling N₂ for 5minutes and then heated under sealed conditions to 95° C. for 14 hrs.Upon cooling to room temperature, the mixture was diluted with ethylacetate, washed with water and brine and dried over Na₂SO₄. The filtratewas then concentrated and purified by silica gel column chromatographyeluting with ethyl acetate/hexane (1/4) to yield4-(2-{[4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyricacid tert-butyl ester (1.1 g). MS [M+H]⁺:514.0; t_(R)=3.24 min (method1)

Step 15D:4-(2-{[4-Chloro-3-(3-cyano-quinolin-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyricAcid Tert-Butyl Ester

A mixture of THF (0.5 mL) and water (0.133 mL) containing4-(2-{[4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyricacid tert-butyl ester (70 mg, 0.14 mmol), 2-chloro-3-methylquinoline (24mg, 0.125 mmol), Pd₂(dba)₃ (11 mg, 0.012 mmol), P(t-Bu)₃HBF₄ (7 mg,0.024 mmol) and KOH (28 mg, 0.5 mmol), was bubbled with N₂ for 5 min andthen heated at 70° C. for 6 hrs. The mixture was diluted with EtOAc,washed with water and brine, dried (Na₂SO₄), filtered and concentratedin vacuo. Purification by silica gel column chromatography (eluentEtOAc/Hexanes: 1/4 with gradient up to EtOAc/Hexanes: 1/1) yielded 20 mgof4-(2-{[4-chloro-3-(3-cyano-quinolin-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyricacid tert-butyl ester. MS: 539.9 (M+H)⁺; t_(R)=2.99 min (method 1).

Step 15E:4-(2-{[4-Chloro-3-(3-cyano-quinolin-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyricAcid

4-(2-{[4-Chloro-3-(3-cyano-quinolin-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyricacid tert-butyl ester (20 mg, 0.037 mmol) was stirred in a mixture ofDCM (0.2 mL) and TFA (0.2 mL) for 1 hr. The mixture was concentrated,dissolved in MeOH and purified by prep LCMS to yield4-(2-{[4-chloro-3-(3-cyano-quinolin-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyricacid 15-1. MS [M+H]⁺:483.9; t_(R)=7.05 min, (method 2)

Example 163-(2-{[4-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-6-methyl-phenoxy)-propionicAcid Ethyl Ester

Step 16A:3-(2-{[4-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-6-methyl-phenoxy)-propionicAcid Ethyl Ester

To a solution of3-(2-{[4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-6-methyl-phenoxy)-propionicacid (160 mg, 0.35 mmol) in DCM (15 mL) was added oxalyl chloride (45.2μL, 0.52 mmol) and 1 drop of DMF. The solution was stirred for 30minutes before addition of ethanol (5 mL). The solution was stirred fora further 30 minutes at which time the solvent was evaporated and theresidue purified by preparative TLC [eluent: 50% ethyl acetate inhexane] to yield3-(2-{[4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-6-methyl-phenoxy)-propionicacid ethyl ester 16-1 (125 mg). MS [M+H]⁺: 492.4; t_(R)=5.45 min.(method 4).

Similarly,3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicacid ethyl ester 16-2 was prepared. MS [M+H]⁺: 532.2; t_(R)=30.78 min.(method 5).

Example 17[[4-Chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoyl]-(2-methoxy-phenyl)-amino]-aceticAcid Methyl Ester

Step 17A:4-Chloro-N-(2-methoxy-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide

A mixture of 3-bromo-4-chloro-N-(2-methoxy-phenyl)-benzamide (2 g, 5.85mmol, Step 2B), bis(pinacolato)diboron (2.23 g, 8.78 mmol), Pd(dppf)₂Cl₂(342 mg, 0.47 mmol), potassium acetate (1.72 g, 17.6 mmol) in dioxane(40 mL) was degassed by bubbling through N₂ for 5 minutes and then washeated under sealed condition to 95° C. for 14 hrs. Upon cooling to roomtemperature, the mix was diluted with ethyl acetate and washed withwater and brine, and was dried over Na₂SO₄. Concentration andpurification by silica gel column chromatography eluting with ethylacetate/hexane (2/3) gave4-chloro-N-(2-methoxy-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(2.3 g). MS [M+H]⁺:387.8; t_(R)=3.15 min. (method 1)

Step 17B:4-Chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide

A solution of 2N Na₂CO₃ (5.85 mL) and Pd(PPh₃)₄ (340 mg, 0.29 mmol) wasadded to a degassed mixture of4-chloro-N-(2-methoxy-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(2.2 g, 5.85 mmol) and 2-bromo-3,5-dichloro-pyridine (1.47 g, 6.44 mmol)in toluene (30 mL) and EtOH (6 mL). The mixture was heated at 100° C.for 12 hrs. Upon cooling to room temperature, the mixture was dilutedwith ethyl acetate and washed with water and brine, and was dried overNa₂SO₄. After filtration and concentration the mixture was taken up inEtOAc, filtered, washed with EtOAc (3×), MeOH and ether to yield 1.6 gof4-chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide.MS [M+H]⁺:406.9; t_(R)=3.03 min. (method 1)

Step 17C:[[4-Chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoyl]-(2-methoxy-phenyl)-amino]-aceticAcid Methyl Ester

To 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide(40 mg, 0.1 mmol) in DMF (0.6 mL) at 0-5° C., NaH (8 mg, 0.2 mmol, 60%in mineral oil) was added and the mixture was stirred for 25 min at rt.Upon addition of bromomethylacetate (21 μL, 0.2 mmol), the mixture wasstirred at room temperature for 12 hrs. Addition of MeOH (0.3 mL) wasfollowed by filtration and purification on preparative HPLC to afford[[4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoyl]-(2-methoxy-phenyl)-amino]-aceticacid methyl ester 17-1.

The following compounds were prepared according to the proceduredescribed above.

MS t_(R) (min) method Ex. R₂ (M + H)⁺ 2 17-1 acetic acid methyl ester478.6 9.92 17-2 ethyl 434.7 8.73 17-3 4-butyric acid methyl ester 506.78.68

Example 184-Chloro-N-cyclopropyl-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide

Step 18A: 3-Bromo-4-chloro-benzoic Acid Methyl Ester

To a suspension of 3-bromo-4-chloro-benzoic acid (10 g, 42.6 mmol) inMeOH (100 mL) cooled with ice bath, was added acetyl chloride (30.4 mL,0.43 mol) dropwise. The mixture was then stirred at room temperature for12 hrs and concentrated to yield 3-bromo-4-chloro-benzoic acid methylester as a yellow solid (10.6 g). NMR (CDCl₃), δ, 8.28 (1H, s), 7.91(1H, brs), 7.52 (1H, brs), 3.92 (3H, s).

Step 18B:4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic AcidMethyl Ester

A mixture of 3-bromo-4-chloro-benzoic acid methyl ester (3.13 g, 12.6mmol), bis(pinacolato)diboron (4.79 g, 18.8 mmol), PdCl₂(dppf)₂ (0.74 g,1.0 mmol), KOAc (3.69 g, 37.7 mmol) in DMF (50 mL) was sealed and heatedat 95° C. for 12 hrs. The mixture was partitioned between ethyl acetateand water. Organic layer was separated, washed with water, brine, driedover MgSO₄. After filtration and concentration, purification by silicagel chromatography eluting with ethyl acetate/hexane (1/9) gave4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester (3.5 g). NMR (DMSO-d₆), δ, 8.19 (1H, d, J=2.1 Hz), 7.99(1H, dd, J=2.1, 8.4 Hz), 7.58 (1H, d, J=8.4 Hz), 3.85 (3H, s), 1.31(12H, s).

Step 18C: 4-Chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic Acid MethylEster

A mixture of 2-bromo-3,5-dichloropyridine (2.72 g, 12 mmol),4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester (1.78 g, 6 mmol)), 2N Na₂CO₃ (9.0 mL, 18 mmol), Pd(PPh₃)₄(0.35 g, 0.3 mmol) in toluene/ethanol (30 mL/6 mL) was sealed and heatedat 90° C. for 12 hrs. The mixture was concentrated and partitionedbetween ethyl acetate and water. The ethyl acetate layer was washed withwater and brine and was dried over MgSO₄. After filtration andconcentration, purification by silica gel chromatography eluting withethyl acetate/hexane (5/95) gave4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid methyl ester (1.8g). MS (M+H)+: 315.6, t_(R)=8.505 min (method 2)

Step 18D: 4-Chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic Acid

A mixture of THF (15 mL) and water (1 mL) containing4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid methyl ester (1.7 g,5.4 mmol) and LiOH.H₂O (0.68 g, 16.1 mmol) was stirred at roomtemperature for 12 hrs. The mixture was acidified and extracted withethyl acetate. The organic layer was washed with brine and water and wasdried. Filtration and concentration gave4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid as a white solid(1.4 g). MS (M+H)⁺: 301.6, t_(R)=7.048 min (method 2)

Step 18E: Cyclopropyl-(2-methoxy-phenyl)-amine

To a mixture of 2-methoxyaniline (3 g, 24.3 mmol), HOAc (100 mL) andMeOH (50 mL), [(1-ethoxycyclo-propyl)oxy]-trimethylsilane (5.6 mL, 28.0mmol) was added dropwise at r.t. The mixture was refluxed at 65° C. for3 hrs and subsequently concentrated in vacuo.

A mixture of NaBH₄ (1.84 g, 48.6 mmol) in anhydrous THF (25 mL) wascooled to 5° C. and BF₃. Et₂O (6.1 mL, 50 mmol) was added dropwise underN₂ atmosphere. The mixture was stirred for 1 hr at 5° C., then the crudeoil from the previous step dissolved in THF (12 mL) was added dropwiseat 5-10° C. in a time period of 20 min. The mixture was stirred at rtovernight and at reflux for 2 hrs, quenched in water (100 mL) andextracted with ether (3×). The combined organic layers were washed withwater, dried (Na₂SO₄), filtered and concentrated to yield 4.1 g ofcyclopropyl-(2-methoxy-phenyl)-amine as an oil which was used withoutfurther purification. MS [M+H]⁺:164.0; t_(R)=2.46 min. (method 1)

Step 18F:4-Chloro-N-cyclopropyl-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide

To 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid (60 mg, 0.2 mmol)in dry DCM (0.6 mL) was added DMF (1 drop) followed by slow addition ofoxalyl chloride (30 μL, 0.34 mmol). The mixture was stirred for 2.5 hrs,then concentrated to yield the corresponding4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoyl chloride which wasdissolved in DCM (1 mL). Cyclopropyl-(2-methoxy-phenyl)-amine (55 mg,0.34 mmol), followed by diisopropylethylamine (71 μL, 0.4 mmol) wereadded slowly. The mixture was stirred at room temperature for 12 hrs,concentrated and purified by preparative LCMS to yield4-chloro-N-cyclopropyl-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide18-1. MS (M+H)⁺: 446.9, t_(R)=8.59 min (method 2)

Example 194-Chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide

Step 19A:4-Chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide

To 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoic acid (100 mg, 0.33mmol) in dry DCM (1 mL), was added DMF (1 drop) followed by addition ofoxalyl chloride (35 μL, 0.40 mmol) slowly. The mixture was stirred for2.5 hrs, then concentrated to yield4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoyl chloride, which wasdissolved in DCM (1 mL). 2-Methylamino-phenol (45 mg, 0.36 mmol) wasadded followed by the slow addition of diisopropylethylamine (88 μL, 0.5mmol). The mixture was stirred at room temperature for 12 hrs,concentrated and purified by preparative TLC (DCM/MeOH=9/1) followed bypreparative LCMS to yield4-chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide19-1. MS (M+H): 409.0, t_(R)=7.55 min (method 2)

The following compounds were prepared according to the proceduredescribed above.

Ex.

MS (M + H)⁺ t_(R) (min) HPLC Method 19-1 2-hydroxy-phenyl 409.0 7.55 219-2 2-methoxy-phenyl 420.8 8.29 2 19-3 3-fluoro-phenyl 410.7 8.40 219-4 4-fluoro-phenyl 409.6 8.34 2 19-5 phenyl 390.7 8.22 2 19-62-benzoic acid methyl ester 448.6 8.06 2 19-7 3-chloro-2-methoxy-phenyl456.6 8.78 2 19-8 2,6-dimethyl-phenyl 418.7 8.90 2 19-9 3-methoxy-phenyl420.7 8.21 2 19-10 2,3-dimethyl-phenyl 418.7 8.90 2

Example 204-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyricAcid

Step 20A: 4-Chloro-2-fluoro-3-nitro-benzoyl Chloride

To 4-chloro-2-fluoro-3-nitro-benzoic acid (5.0 g, 22.8 mmol) suspendedin dry DCM (60 mL), was added DMF (0.5 mL) followed by the slow additionof oxalyl chloride (2.4 mL, 27.3 mmol, 2M in DCM). The mixture wasstirred for 2 hrs, then concentrated to yield4-chloro-2-fluoro-3-nitro-benzoyl chloride as a yellow solid.

Step 20B: 4-Chloro-2-fluoro-N-methyl-5-nitro-N-o-tolyl-benzamide

To 4-chloro-2-fluoro-3-nitro-benzoyl chloride in DCM (60 mL) cooled witha ice bath, triethylamine (6.3 mol, 45.5 mmol) was added slowly,followed by the dropwise addition of N-methyl-o-toluidine (3.8 mL, 27.3mmol). The ice bath was removed and the mixture was stirred for 12 hrs,followed by partition between DCM and water. The organic layer was thenwashed with 1 N HCl, saturated NaHCO₃ and brine and was dried overMgSO₄. Concentration yielded4-chloro-2-fluoro-N-methyl-5-nitro-N-o-tolyl-benzamide as a yellow solid(6.6 g). MS: 322.8 (M+H)⁺: t_(R)=2.42 min (method 1);

Step 20C: 5-Amino-4-chloro-2-fluoro-N-methyl-N-o-tolyl-benzamide

To 4-chloro-2-fluoro-N-methyl-5-nitro-N-o-tolyl-benzamide (6.6 g, 20.3mmol) was stirred vigorously in a mixture of water (30 mL) and THF (30mL) containing Na₂S₂O₄ (17.6 g, 101.2 mmol) for 12 hrs. The organiclayer was then separated and the water layer was further extracted withethyl acetate. The combined organic solutions were washed with brine anddried over MgSO₄. Concentration yielded5-amino-4-chloro-2-fluoro-N-methyl-N-o-tolyl-benzamide as a crude solidwhich was washed with ether to give a light yellow product (3.3 g). MS:292.9 (M+H)⁺: t_(R)=1.90 min (method 1)

Step 20p: 5-Bromo-4-chloro-2-fluoro-N-methyl-N-o-tolyl-benzamide

To a solution of acetonitrile (45.0 mL) containing CuBr₂ (3.2 g, 14.3mmol) and n-butylnitrite (1.7 mL, 14.3 mmol) heated at 65° C. withstirring, was added5-amino-4-chloro-2-fluoro-N-methyl-N-o-tolyl-benzamide (3.2 g, 11.0mmol) in acetonitrile (10.0 mL) dropwise. After 2 hours the mixture wascooled to room temperature and was partitioned between ethyl acetate andwater. The organic layer was separated, washed with 1N HCl, sat. NaHCO₃and brine, dried over MgSO₄ and filtered. Concentration gave an oilwhich was purified by silica gel column chromatography eluting withethyl acetate in hexanes (1/5) to give5-bromo-4-chloro-2-fluoro-N-methyl-N-o-tolyl-benzamide as a light yellowoil (3.1 g). MS: 355.8 (M+H)⁺; t_(R)=2.61 min (method 1)

Step 20E: 5-Bromo-4-chloro-2-methoxy-N-methyl-N-o-tolyl-benzamide

A mixture of 5-bromo-4-chloro-2-fluoro-N-methyl-N-o-tolyl-benzamide (2.5g, 7.0 mmol) was heated in MeONa/MeOH (20 mL, 25%) at 55° C. for 12 hrs,then was concentrated and partitioned between DCM and water. The organiclayer was then separated, washed with 3N HCl, sat NaHCO₃ and brine,dried over MgSO₄, and concentrated. Purification by silica gel columnchromatography eluting with ethyl acetate in hexanes (1/4) gave5-bromo-4-chloro-2-methoxy-N-methyl-N-o-tolyl-benzamide (2.75 g). MS:367.8 (M+H)⁴; t_(R)=2.51 min (method 1).

Step 20F: 5-Bromo-4-chloro-2-hydroxy-N-methyl-N-o-tolyl-benzamide

To a solution of DCM (15.0 mL) containing5-bromo-4-chloro-2-methoxy-N-methyl-N-o-tolyl-benzamide (2.75 g, 7.5mmol) at −78° C., was added BBr₃ (38.0 mL, 1M in DCM) dropwise. Themixture was gradually warmed to room temperature and stirred for 12 hrs.The mixture was concentrated to yield a solid which was washed by etherto give 5-bromo-4-chloro-2-hydroxy-N-methyl-N-o-tolyl-benzamide (2.6 g).MS: 353.8 (M+H)⁺; t_(R)=2.50 min (method 1).

Step 20G:4-[4-Bromo-5-chloro-2-(methyl-o-tolyl-carbamoyl)-phenoxyl]-butyric AcidTert-Butyl Ester

To 5-bromo-4-chloro-2-hydroxy-N-methyl-N-o-tolyl-benzamide (2.6 g, 7.3mmol) in dry DMF (30 mL), was added K₂CO₃ (2.0 g, 7.6 mmol), followed byaddition of t-butyl 4-bromobutyrate (2.0 g, 8.8 mmol). The mixture washeated at 60° C. for 12 hrs and partitioned between ethyl acetate andwater. The organic layer was separated, washed with water and brine, anddried over MgSO₄. After filtration, concentration and purification bysilica gel column chromatography eluting with ethyl acetate in hexanes(3/7) gave4-[4-bromo-5-chloro-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyric acidtert-butyl ester (3.0 g). MS: 496.3 (M+H)⁺; t_(R)=2.81 min (method 1).

Step 20H:4-[5-chloro-2-(methyl-o-tolyl-carbamoyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butyricAcid Tert-Butyl Ester

A mixture of4-[4-bromo-5-chloro-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyric acidtert-butyl ester (3.0 g, 6.1 mmol), bis(pinacolato)diboron (2.3 g, 9.1mmol), PdCl₂(dppf)₂ (354.0 mg, 0.48 mmol) and potassium acetate (1.78 g,18.2 mmol) in dioxane (30 mL) was sealed after degassed with N₂ for 5min, and heated at 95° C. for 12 hrs. The mixture was filtered throughcelite to remove solids. The celite was washed by ethyl acetate severaltimes. The combined solution was washed with water and brine, dried overMgSO₄ and filtered. Concentration and purification by silica gel columnchromatography eluting with ethyl acetate in hexanes (1/5) gave4-[5-chloro-2-(methyl-o-tolyl-carbamoyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butyricacid tert-butyl ester (3.0 g). MS: 544.0 (M+H)⁺; t_(R)=2.90 min (method1).

Step 20I:4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyricAcid Tert-Butyl Ester

4-[5-Chloro-2-(methyl-o-tolyl-carbamoyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butyricacid tert-butyl ester (444.0 mg, 0.8 mmol),5-bromo-2-trifluoromethyl-isonicotinonitrile (171.0 mg, 0.7 mmol),Pd(Ph₃P)₄ (78.6 mg, 0.07 mmol), Na₂CO₃ (432.0 mg, 4.1 mmol) in dioxane(9 mL) and water (1 mL) was degassed with N₂ for 5 min, sealed, andheated at 100° C. for 12 hrs. The mixture was then partitioned betweenethyl acetate and water. The organic layer was washed with water andbrine, dried over MgSO₄ and filtered. Concentration and purification byTLC plates eluting with ethyl acetate in hexanes (2/3) and again withTLC plates eluting with acetonitrile/dichloromethane (1/9) gave4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyricacid tert-butyl ester (410 mg). MS: 588.7 (M+H)⁺; t_(R)=11.05 min(method 3).

Step 20J:4-[5-Chloro-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyricAcid

4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyricacid tert-butyl ester (410 mg, 0.7 mmol) was stirred in a mixture oftrifluoroacetic acid in DCM (1/1, 3 mL) for 2 hrs. Concentrationfollowed by purification by HPLC gave4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyricacid 20-1 (62 mg). MS: 532.6 (M+H)⁺; t_(R)=5.29 min (method 3). NMR(CDCl₃, reported as the major isomer of cis-trans amide rotamers), δ,8.54 (1H, s), 7.94 (1H, s), 7.34-7.25 (1H, m), 7.18-7.14 (2H, m),7.14-7.04 (1H, m), 7.02 (1H, s), 6.92 (1H, s), 4.08 (2H, t, J=6.3 Hz),3.40 (3H, s), 2.62 (2H, t, J=6.3 Hz), 2.30-2.18 (2H, m), 2.57 (3H, s).

The following compounds were similarly prepared to Example 20-1:

MS t_(R) HPLC Ex. A alkyl (M + H)⁺ (min) Method 20-1 4-cyano-6- —(CH₂)₃—532.6 5.29 3 trifluoromethyl- pyridin-3-yl 20-2 4,6-dichloro-pyridin-—(CH₂)₃— 506.8 4.95 2 3-yl 20-3 3-cyano-quinolin-2-yl —(CH₂)₃— 513.94.60 2

Example 21-14-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-hydroxy-butoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide

Step 21A: 5-Amino-4-chloro-2-fluoro-benzoic Acid Methyl Ester

SOCl₂ (10.0 mL, 137.0 mmol) was added slowly to an ice bath cooledmixture of 4-chloro-2-fluoro-3-nitro-benzoic acid (25.0 g, 114.2 mmol)in MeOH (200 mL). The mixture was heated at 70° C. for 16 hrs thenconcentrated to yield 4-chloro-2-fluoro-5-nitro-benzoic acid methylester (24.9 g, 0.11 mmol), which was resuspended in a mixture of THF(200 mL) and water (200 mL). Na₂S₂O₄ (139.4 g, 0.80 mol) was added withvigorous stirring. After stirring for 2 hours, the mixture was extractedwith ethyl acetate and the organic layer was washed with water and driedover Na₂SO₄. The filtrate was concentrated to give5-amino-4-chloro-2-fluoro-benzoic acid methyl ester (15.1 g). MS: 203.9(M+H)⁺; t_(R)=1.67 min (method 1).

Step 21B: 5-Bromo-4-chloro-2-fluoro-benzoic Acid Methyl Ester

Isoamyl nitrite (12.7 mL, 94.8 mmol) was added to5-amino-4-chloro-2-fluoro-benzoic acid methyl ester (14.8 g, 72.9 mmol)in acetonitrile (280 mL), followed by addition of CuBr₂ (21.1 g, 94.8mmol). Then the mixture was heated at 65° C. with stirring for 2 hrs,followed by partition between ethyl acetate and water. The organic layerwas then washed with saturated NaHCO₃ and brine and was dried overNa₂SO₄. The filtrate was concentrated and purified by silica gelchromatography eluting with ethyl acetate/hexane (1/1) to yield5-bromo-4-chloro-2-fluoro-benzoic acid methyl ester (14.0 g). MS: 268.0(M⁺) from GC-MS; t_(R)=2.53 min (method 1);

Step 21: 5-Bromo-4-chloro-2-fluoro-benzoic Acid

5-Bromo-4-chloro-2-fluoro-benzoic acid methyl ester (14.0 g, 52.4 mmol)was stirred vigorously in a mixture of THF (250 ml) and 1N NaOH (200 ml)for 16 hrs. The mixture was acidified to pH 3 with 6N HCl, concentratedpartially to remove THF and then extracted with ethyl acetate. Theorganic phase was washed with water and brine and was dried over Na₂SO₄.The filtrate was concentrated to yield 5-bromo-4-chloro-2-fluoro-benzoicacid (13.3 g).

Step 21D: 5-Bromo-4-chloro-2-fluoro-benzoyl Chloride

5-Bromo-4-chloro-2-fluoro-benzoic acid (13.3 g, 52.6 mmol) was convertedto 5-bromo-4-chloro-2-fluoro-benzoyl chloride (14.0 g) using theprocedure of Step 2A.

Step 21E:5-Brom-4-chloro-2-fluoro-N-(2-methoxy-6-methyl-phenyl)-benzamide

5-Bromo-4-chloro-2-fluoro-N-(2-methoxy-6-methyl-phenyl)-benzamide (9.1g) as a white solid was obtained from the corresponding5-bromo-4-chloro-2-fluoro-benzoyl chloride (7.0 g, 25.8 mmol) using theprocedure of Step 2B. MS: 373.8 (M+H)⁺, t_(R)=2.54 min (method 1).

Step 21F:5-Bromo-4-chloro-2-fluoro-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide

5-Bromo-4-chloro-2-fluoro-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide(9.0 g) was obtained from the corresponding5-bromo-4-chloro-2-fluoro-N-(2-methoxy-6-methyl-phenyl)-benzamide (9.1g, 24.5 mmol) using the procedure of Step 2C. MS: 387.8 (M+H)⁺,t_(R)=2.60 min (method 1).

Step 21G:5-bromo-4-chloro-2-(4-hydroxy-butoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide

NaH (373 mg, 9.3 mmol, 60% in mineral oil) was added to 1,4-butanediol(3.5 g, 38.9 mmol) in dry DMF (50 mL). The mixture was stirred at roomtemperature for 15 minutes.5-Bromo-4-chloro-2-fluoro-N-(2-methoxy-6-methyl-phenyl)-benzamide (3.0g, 7.8 mmol) in DMF (25 mL) was added slowly. The mixture was thenheated at 50° C. for 2 hrs, cooled to room temperature and partitionedbetween DCM and water. The organic layer was separated, washed with 1HHCl, sat NaHCO₃ and brine, then dried over Na₂SO₄. The filtrate wasconcentrated and the residue purified using column chromatography with agradient of 50% ethyl acetate in hexanes to 100% ethyl acetate to yield5-bromo-4-chloro-2-(4-hydroxy-butoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide(2.3 g). MS: 457.9 (M+H)⁺, t_(R)=2.38 min (method 1).

Step 21H:4-Chloro-2-(4-hydroxy-butoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide

4-Chloro-2-(4-hydroxy-butoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide(2.0 g) was obtained from the corresponding5-bromo-4-chloro-2-(4-hydroxy-butoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide(2.3 g, 5.0 mmol) using the procedure of Step 2D. MS: 504.1 (M+H)⁺,t_(R)=2.54 min (method 1).

Step 21I:4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-hydroxy-butoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide

4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-hydroxy-butoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide21-1 was obtained from4-chloro-2-(4-hydroxy-butoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamideusing the Suzuki procedure of Step 2E1. MS: 548.0 (M+H)⁺, t_(R)=2.46 min(method 1).

The following examples were prepared according to the above procedure.

MS (M + t_(R) HPLC Ex. A R₃ alkyl H)⁺ (min) Method 21-1 4-cyano-6-methoxy —(CH₂)₄— 548.0 5.95 4 trifluoromethyl- pyridin-3-yl 21-26-cyano-4-methyl- methoxy —(CH₂)₄— 493.9 7.08 2 pyridin-3-yl 21-33-cyano-quinolin- methoxy —(CH₂)₄— 529.9 7.33 2 2-yl 21-4 4-cyano-6-methyl —(CH₂)₄— 532.2 5.78 4 trifluoromethyl- pyridin-3-yl 21-56-cyano-4-methyl- methyl —(CH₂)₄— 478.2 5.38 4 pyridin-3-yl 21-63-cyano-quinolin- methyl —(CH₂)₄— 514.2 5.54 4 2-yl 21-7 4-cyano-6-methoxy —(CH₂)₂— 520.1 4.11 4 trifluoromethyl- pyridin-3-yl 21-84-cyano-6- methoxy —(CH₂)₃— 534 .1 7.62 2 trifluoromethyl- pyridin-3-yl

Example 224-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-6-methyl-phenyl)-methyl-carbamoyl]-phenoxy}-butyricAcid

Step 22A:4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-6-methyl-phenyl)-methyl-carbamoyl]-phenoxy}-butyricAcid

4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-6-methyl-phenyl)methyl-carbamoyl]-phenoxy}-butyric acid (12.6 mg) was obtained fromoxidation of4-chlor-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-hydroxy-butoxy)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide22-1 (40.0 mg, 0.07 mmol) according to the procedure provided in Step11A. MS: 561.9 (M+H)⁺, t_(R)=7.84 min (method 2).

The following examples were prepared according to the above procedure.

MS (M + t_(R) HPLC Ex. A R₃ alkyl H)⁺ (min) Method 22-1 4-cyano-6-methoxy —(CH₂)₃— 561.9 7.84 2 trifluoromethyl- pyridin-3-yl 22-26-cyano-4-methyl- methoxy —(CH₂)₃— 507.9 7.17 2 pyridin-3-yl 22-33-cyano-quinolin- methoxy —(CH₂)₃— 543.9 7.41 2 2-yl 22-4 4-cyano-6-methyl —(CH₂)₃— 546.1 4.73 4 trifluoromethyl- pyridin-3-yl 22-56-cyano-4-methyl- methyl —(CH₂)₃— 492.2 3.93 4 pyridin-3-yl 22-63-cyano-quinolin- methyl —(CH₂)₃— 528.2 4.42 4 2-yl 22-7 4-cyano-6-methyl —(CH₂)₃— 546.1 4.73 4 trifluoromethyl- pyridin-3-yl 22-86-cyano-4-methyl- methyl —(CH₂)₃— 492.2 3.93 4 pyridin-3-yl 22-94-cyano-6- methoxy —CH₂— 533.9 4.95 4 trifluoromethyl- pyridin-3-yl22-10 4-cyano-6- methoxy —(CH₂)₂— 548.1 2.66 2 trifluoromethyl-pyridin-3-yl

Example 232-(3-Amino-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide

Step 23A:2-(3-Amino-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide

Triethylamine (22 μL, 0.157 mmol) and diphosphorylazide (33.9 □μL, 0.157mmol) were added to4-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-6-methyl-phenyl)methyl-carbamoyl]-phenoxy}-butyric acid 22-1 (80 mg, 0.157 mmol) indioxane (2 mL). The mixture was heated at 100° C. for 16 hrs, thencooled to room temperature and stirred with 6N HCl (1 mL) for 1 hr. TheDCM layer was separated, concentrated and the residue was dissolved inMeOH and purified by HPLC-MS to afford2-(3-amino-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide23-1 as a TFA salt (40 mg). MS: 533.0 (M+H)⁺, t_(R)=5.38 min (method 4).

Example 245-{2-Chloro-5-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-pyridine-2-carboxylicAcid Amide

Step 24A:5-{2-Chloro-5-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-pyridine-2-carboxylicAcid Amide

To a solution of4-chloro-3-(6-cyano-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide2-2 (29 mg, 0.077 mmol) in THF (0.5 mL), 1N LiOH (0.5 mL) and K₂CO₃ (10mg, 0.073 mmol) were added. After stirring for 48 hrs at roomtemperature, EtOAc and water were added. The aqueous layer was removedand the organic layer was concentrated, dissolved in MeOH and subjectedto preparative LCMS to yield5-{2-chloro-5-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-pyridine-2-carboxylicacid amide 24-1. MS (M+H)⁺: 396.0, t_(R)=5.93 min (method 2).

Similarly,5-{2-chloro-5-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-4-methyl-pyridine-2-carboxylicacid amide 24-2 was prepared from the corresponding4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide2-10. MS (M+H)⁺: 410.0, t_(R)=6.12 min (method 2).

Example 254-Chloro-N-(2-methoxy-6-methyl-phenyl)-N-methyl-3-(4-methyl-6-pyrazol-1-yl-pyridin3-yl)-benzamide

Step 25A:4-Chloro-N-(2-methoxy-6-methyl-phenyl)-N-methyl-3-(4-methyl-6-pyrazol-1-yl-pyridin3-yl)-benzamide

A mixture of4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide2-31 (66.0 mg, 0.16 mmol) and pyrazole (12.9 mg, 0.19 mmol) was added toCuI (6.0 mg, 0.032 mmol), K₂CO₃ (43.9 mg, 0.32 mmol) andN,N′-dimethyethylenediamine (1.4 mg, 0.016 mmol) in dioxane (1 mL). Thereaction vessel was sealed and heated at 130° C. for 24 hrs. The mixturewas then filtered and purified by HPLC giving4-chloro-N-(2-methoxy-6-methyl-phenyl)-N-methyl-3-(4-methyl-6-pyrazol-1-yl-pyridin3-yl)-benzamide 25-1 (4.5 mg). MS (M+H)⁺: 446.8, t_(R)=8.60 min (method2).

Similarly,4-Chloro-3-(6-imidazol-1-yl-4-methyl-pyridin-3-yl)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide25-2 was prepared. MS (M+H)⁺: 446.8, t_(R)=5.24 min (method 2).

Example 264-Chloro-N-(2-methoxy-6-methyl-phenyl)-N-methyl-3-(4-methyl-6-methyl-sulfanylpyridin-3-yl)-benzamide

Step 26A: 4-Chloro-N-(2-meoxy-6-methyl-phenyl)-N-methyl-3-(4-methyl-6-methyl-sulfanylpyridin-3-yl)-benzamide

A mixture of4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2-methoxy-6-methyl-phenyl)-N-methyl-benzamide2-31 (20.0 mg, 0.048 mmol) and sodium thiomethoxide (3.3 mg, 0.048 mmol)in DMSO (1 mL) was heated at 80° C. for 1 hr. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated and purified by HPLC yielding4-chloro-N-(2-methoxy-6-methyl-phenyl)-N-methyl-3-(4-methyl-6-methyl-sulfanylpyridin-3-yl)-benzamide(4.3 mg). MS (M+H)⁺: 426.9; t_(R)=7.92 min. (method 2).

Example 274-Chloro-3-(3,5-dichloro-1-oxy-pyridin-2-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide

Step 27A:4-Chloro-3-(3,5-dichloro-1-oxy-pyridin-2-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide

A mixture of4-chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide19-2 (30.0 mg, 0.066 mmol), hydrogen peroxide (10 μL, 33% in water) andacetic acid (0.2 mL) was heated under reflux for 48 hrs followed byaddition of more hydrogen peroxide (10 μL, 33% in water). The mixturewas then refluxed for another 24 hrs. The mixture was purified by HPLCgiving4-chloro-3-(3,5-dichloro-1-oxy-pyridin-2-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide(12.3 mg). MS (M+H)⁺: 436.6; t_(R)=6.52 min. (method 2).

Example 284-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[3-(1H-tetrazol-5-yl)-propoxy]-phenyl}-benzamide

Step 28A:3-Bromo-4-chloro-N-[2-(3-cyano-propoxy)-phenyl]-N-methyl-benzamide

CsCO₃ (5.17 g, 15.87 mmol) was added to a solution of4-bromobutyronitrile (0.63 mL, 6.35 mmol) and3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (1.80 g, 5.29mmol, Step 3B) in DMF (20 mL). The mixture was stirred at roomtemperature for approximately 16 hrs and was partitioned between ethylacetate and water. The ethyl acetate layer was separated, washed withwater and brine, and was dried over MgSO₄. The organic filtrate wasevaporated to yield3-bromo-4-chloro-N-[2-(3-cyano-propoxy)-phenyl]-N-methyl-benzamide as alight yellow solid (2.0 g). MS [M+H]⁺: 408.9; t_(R)=2.39 min. (method 1)

Step 28B:3-Bromo-4-chloro-N-methyl-N-{2-[3-(1H-tetrazol-5-yl)-propoxy]-phenyl}-benzamide

A mixture of3-bromo-4-chloro-N-[2-(3-cyano-propoxy)-phenyl]-N-methyl-benzamide (2.0g, 4.9 mmol), azidotributyltin (4.03 mL, 14.7 mmol) and triethylaluminum(7.74 mL, 14.7 mmol, 25% in toluene) in toluene (25 mL) was heated at80° C. for 5 hrs. The mixture was allowed to cool to room temperatureand was acidified with 1N HCl. The mixture was extracted with DCM. Theorganic layer was washed with water and brine, and was dried. Thefiltrate was concentrated in vacuo and the residue purified by silicagel column chromatography (eluent: 3% MeOH in DCM) to afford3-bromo-4-chloro-N-methyl-N-{2-[3-(1H-tetrazol-5-yl)-propoxy]-phenyl}-benzamide(1.93 g). MS [M+H]⁺: 451.9; t_(R)=2.26 min. (method 1)

Step 28C:3-Bromo-4-chloro-N-methyl-N-(2-{3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-tetrazol-5-yl]-propoxy}-phenyl)-benzamideand3-bromo-4-chloro-N-methyl-N-(2-{3-[2-(2-trimethylsilanyl-ethoxymethyl)-1H-tetrazol-5-yl]-propoxy}-phenyl)-benzamide

To3-bromo-4-chloro-N-methyl-N-{2-[3-(1H-tetrazol-5-yl)-propoxy]-phenyl}-benzamide(1.90 g, 4.2 mmol) in DMF (20 mL) was added2-(trimethylsilyl)ethoxymethyl chloride (0.89 mL, 5.1 mmol) in oneportion, followed by addition of K₂CO₃ (1.16 g, 8.4 mmol). The mixturewas stirred at room temperature for approximately 16 hrs and then waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with water and brine, and was dried over MgSO₄. Thefiltrate was then concentrated in vacuo and the residue purified bysilica gel column chromatography (eluent: 30% ethyl acetate in hexane)to afford3-bromo-4-chloro-N-methyl-N-(2-{3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-tetrazol-5-yl]-propoxy}-phenyl)-benzamideand3-bromo-4-chloro-N-methyl-N-(2-{3-[2-(2-trimethylsilanyl-ethoxymethyl)-1H-tetrazol-5-yl]-propoxy}-phenyl)-benzamideas two regioisomers (upper spot: 736 mg and lower spot: 785 mg). MS[M+H]⁺: 582.0; t_(R)=2.92 min. (method 1) for upper spot and MS [M+H]⁺:582.0; t_(R)=2.75 min. (method 1) for lower spot.

Step 28D:4-Chloro-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(2-{3-[1or2-(2-trimethylsilanyl-ethoxymethyl)-1H-tetrazol-5-yl]-propoxy}-phenyl)-benzamide

The regioisomer corresponding to the upper spot from Step 28C (736 mg,1.27 mmol) was converted into the corresponding4-chloro-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(2-{3-[1or2-(2-trimethylsilanyl-ethoxymethyl)-1H-tetrazol-5-yl]-propoxy}-phenyl)-benzamide(800 mg) using the procedure of Step 2D. MS [M+H]⁺: 628.1; t_(R)=2.98min. (method 1).

Step 28E:4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-(2-{3-[1or2-(2-trimethylsilanyl-ethoxymethyl)-2H-tetrazol-5-yl]-propoxy}-phenyl)-benzamide

4-Chloro-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(2-{3-[1or2-(2-trimethylsilanyl-ethoxymethyl)-1H-tetrazol-5-yl]-propoxy}-phenyl)-benzamide(400 mg) was converted into4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-(2-{3-[1or2-(2-trimethylsilanyl-ethoxymethyl)-2H-tetrazol-5-yl]-propoxy}-phenyl)-benzamide(278 mg) using the Suzuki procedure of Step 2E1. MS [M+H]⁺: 672.0;t_(R)=2.90 min. (method 1).

Step 28F:4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[3-(1H-tetrazol-5-yl)-propoxy]-phenyl}-benzamide

4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-(2-{3-[1or2-(2-trimethylsilanyl-ethoxymethyl)-2H-tetrazol-5-yl]-propoxy}-phenyl)-benzamide(150 mg, 0.22 mmol) was heated to 70° C. in ethanol (1.0 mL) containingconcentrated HCl (0.1 mL) for 30 min. Concentration and purification byHPLC afforded4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[3-(1H-tetrazol-5-yl)-propoxy]-phenyl}-benzamide(72 mg). MS [M+H]⁺: 542.0; t_(R)=4.83 min. (method 4).

Example 295-{2-Chloro-5-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-pyridine-2-carboxylicAcid Amide

Step 29A: N-(2-Chloro-3-fluoro-phenyl)-formamide

A solution of acetic anhydride (10 mL, 106 mmol) and formic acid (30 mL,795 mmol) was stirred at room temperature for 10 mins.2-Chloro-3-fluoroaniline (2.9 g, 20 mmol) was added and the reactionmixture was stirred at 60° C. for 1.5 h. After cooling to roomtemperature, the solvents were removed in vacuo and the residue wasredissolved in DCM (100 mL) and was washed with sat aq. NaHCO₃ until theaqueous phase had a measured pH of 8. The organic layer was furtherwashed with water (2×100 mL), separated and dried over MgSO₄. Filtrationand concentration in vacuo gave N-(2-chloro-3-fluoro-phenyl)-formamide(3.3 g, 95%) as a colorless solid which did not require furtherpurification. MS (M+H)⁺: 173.9, t_(R)=2.04 min (method 1).

Step 29B: N-Methyl-2-chloro-3-fluoroaniline

To a stirred suspension of 95% lithium aluminum hydride (2.19 g, 58mmol) in anhydrous THF (10 mL) at 0° C., was added dropwise a solutionof N-(2-chloro-3-fluoro phenyl)-formamide (2.3 g, 13.2 mmol) inanhydrous THF (20 mL). The reaction mixture was allowed to slowly warmto room temperature and was stirred for a further 40 mins. The mixturewas cooled to 0° C. and was quenched via the sequential addition ofwater (4 mL), 15% aq. NaOH (2 mL), then water (4 mL). Organics wereextracted into a mixture of 3:1 DCM:IPA (100 mL) and washed with water(50 mL). The organic layer was separated and dried over MgSO₄.Filtration then concentration in vacuo gaveN-methyl-2-chloro-3-fluoroaniline 29-1 (2.07 g, 99%) as a yellow oil. MS(M+H)⁺: 160.1, t_(R)=2.21 min (method 1).

The following compounds were prepared according to the two stepprocedure outlined above, using the corresponding commercially availableanilines.

MS t_(R) HPLC Ex. (M + H)⁺ (min) Method 29-1(2-Chloro-3-fluoro-phenyl)-methyl- 160.1 2.21 1 amine 29-2(3-Chloro-5-fluoro-phenyl)-methyl- 159.1 2.43 1 amine 29-3(4-Fluoro-2-methyl-phenyl)-methyl- 140.1 0.98 1 amine 29-4(3,4-Difluoro-phenyl)-methyl-amine 144.0 1.59 1 29-5(3,5-Difluoro-phenyl)-methyl-amine 144.0 2.29 1 29-6(3-Chloro-4-fluoro-phenyl)-methyl- 158.0 0.88 1 amine 29-7(3-Fluoro-2-methyl-phenyl)-methyl- 140.1 1.93 1 amine 29-8(3-Fluoro-2-methoxy-phenyl)-methyl- 155.9 1.97 1 amine 29-9(2-Chloro-5-fluoro-phenyl)-methyl- 159.9 2.79 1 amine 29-10(2-methoxy-6-methyl-phenyl)- 152.1 1.07 1 methyl-amine 29-11(2,6-Dimethyl-phenyl)-methyl-amine 136.1 0.65 1 29-12(3-Chloro-2-methyl-phenyl)-methyl- 155.9 2.45 1 amine 29-13(2,3-Difluoro-phenyl)-methyl-amine 144.0 2.53 1

Example 304-Chloro-N-(2-chloro-3-fluoro-phenyl)-N-methyl-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzamide

Step 30A: 4-Chloro-3-ureido-benzoic Acid

A stirred solution of 3-amino-4-chlorobenzoic acid (34.2 g, 200 mmol)and urea (24 g, 400 mmol) in glacial acetic acid (200 mL) was heated at100° C. for 24 h. The mixture was allowed to cool to room temperatureand the resulting precipitate was separated by filtration, washed withwater (2×100 mL) and diethyl ether (2×100 mL), then air dried to give 35g of 4-chloro-3-ureido-benzoic acid as a grey solid that was carried onwithout further purification.

Step 30B:4-Chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoicAcid Ethyl Ester

To a stirred suspension of 4-chloro-3-ureido-benzoic acid (26 g, 121mmol) in ethanol (375 mL) was added 1,1,1-trifluoro-2,4-pentanedione (28g, 182 mmol) and concentrated (95%) sulfuric acid (50 mL). The reactionmixture was heated at 85° C. for 6 h. After cooling to room temperature,the mixture was partitioned between water (500 mL) and DCM (1 L) and tothis was added 6N aq. NaOH, until pH 9-10 attained. The DCM layer wasseparated and dried over MgSO₄ and filtered. Concentration in vacuo gavean orange oil which was purified via silica gel flash chromatography(eluting with a gradient of 10% to 25% EtOAc in hexanes). The resultingorange solid was further triturated with diethyl ether to give4-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoicacid ethyl ester (3.77 g, 9%) as a colorless solid. MS (M+H)⁺: 360.8,t_(R)=2.670 min (method 1); ¹H NMR (CDCl₃) δ 8.16 (1H, dd, J=8.4, 2.1Hz), 8.00 (1H, d, J=1.8 Hz), 7.70 (1H, d, J=8.4 Hz), 6.63 (1H, s), 4.39(2H, q, J=6.9 Hz), 2.15 (3H, s), 1.39 (3H, t, J=6.9 Hz).

Step 30C:4-Chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoicAcid

A stirred suspension of4-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoicacid ethyl ester (3.34 g, 9.26 mmol) in 12N aq. HCl solution (10 mL) washeated at 85° C. for 1 h. After cooling to room temperature the organicswere extracted into DCM (3×100 mL). The combined organic layer was driedover MgSO₄ and filtered. Concentration in vacuo gave a yellow solidwhich was purified via silica gel flash chromatography (eluting with agradient of 5% to 10% MeOH in DCM, followed by 9% MeOH and 1% AcOH inDCM) to give4-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoicacid (1.0 g, 33%) as a cream solid. MS (M+H)⁺: 332.8, t_(R)=2.364 min(method 1); ¹H NMR (CDCl₃) δ 8.17 (1H, dd, J=8.4, 2.4 Hz), 8.04 (1H, d,J=1.5 Hz), 7.72 (1H, d, J=8.4 Hz), 6.72 (1H, s), 2.17 (3H, s).

Step 30D:4-Chloro-N-(2-chloro-3-fluoro-phenyl)-N-methyl-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzamide

To a stirred solution of4-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoicacid (50 mg, 0.151 mmol) in anhydrous 1,2-dichloroethane (0.5 mL) atroom temperature was added oxalyl chloride (23 mg, 0.181 mmol) followedby a catalytic amount of DMF. After stirring for 40 mins, a solution ofN-methyl-2-chloro-3-fluoroaniline 29-1 (30 mg, 0.188 mmol) in1,2-dichloroethane (0.5 mL), followed by 4-(dimethylamino)pyridine (22mg, 0.179 mmol) were added and the mixture was stirred for 12 h. Directpurification via reverse phase preparative LCMS gave4-chloro-N-(2-chloro-3-fluoro-phenyl)-N-methyl-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzamide30-1 (18 mg, 25%) as a colorless solid. MS: 350.5, t_(R)=8.75 min(method 3); ¹H NMR (CDCl₃) δ 7.50 (1H, m), 7.44 (1H, dd, J=8.4, 1.8 Hz),7.31 (1H, m), 7.26 (1H, s), 6.95 (1H, dd, J=9, 2.1 Hz), 6.79 (1H, m),6.55 (1H, s), 3.46 (3H, s), 1.93 (3H, s).

The following compounds were prepared according to the proceduredescribed above.

Ex. R₄

Ob- served mass t_(R) (min) HPLC Method 30-1 trifluoro-2-chloro-3-fluoro- 350.5 8.75 3 methyl phenyl 30-2 trifluoro-3-chloro-5-fluoro- 363.7 9.08 3 methyl phenyl 30-3 trifluoro-4-fluoro-2-methyl- 452.8 6.95 2 methyl phenyl 30-4 trifluoro-3,4-difluoro-phenyl 343.8 7.19 3 methyl 30-5 trifluoro-3,5-difluoro-phenyl 330.1 6.29 3 methyl 30-6 trifluoro-3-chloro-4-fluoro- 313.7 8.53 3 methyl phenyl 30-7 trifluoro-3-fluoro-2-methyl- 453.8 6.95 3 methyl phenyl 30-8 trifluoro-3-fluoro-2-methoxy- 340.2 8.06 3 methyl phenyl 30-9 trifluoro-2-chloro-5-fluoro- 474.2 8.53 3 methyl phenyl 30-10 trifluoro-2-methoxy-6-methyl- 465.6 8.46 3 methyl phenyl 30-11 trifluoro-2,6-dimethyl-phenyl 450.2 8.63 3 methyl 30-12 trifluoro-3-chloro-2-methyl- 469.8 7.28 3 methyl phenyl 30-13 trifluoro-2,3-difluoro-phenyl 457.9 8.15 3 methyl 30-14 trifluoro-2,3-dimethyl-phenyl 449.8 7.03 2 methyl 30-15 trifluoro-2-methoxy-phenyl 451.7 6.47 2 methyl 30-16 trifluoro- 2-fluoro-phenyl439.7 6.48 2 methyl 30-17 trifluoro- 3-fluoro-phenyl 439.7 6.57 2 methyl30-18 methyl 2,3-dimethyl-phenyl 395.8 5.25 2

Example 314-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethoxy]-phenyl}-benzamide

Step 31A:N′-[3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionyl]-hydrazinecarboxylicAcid Tert-Butyl Ester

EDCl (19.9 mg, 0.104 mmol) was added to a solution of3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicacid 11-4 (36.3 mg, 0.069 mmol), t-butyl carbazate (13.7 mg, 0.104mmol), HOBt (14.0 mg, 0.104 mmol) and Na₂CO₃ (8.7 mg, 0.104 mmol) in amixture of DMF (1 mL) and dichloromethane (4 mL). The mixture wasstirred at room temperature for approximately 16 hrs and was partitionedbetween ethyl acetate and water. The ethyl acetate layer was separated,washed with water and brine, and was dried over MgSO₄. The organicfiltrate was evaporated and purified by prep. TLC plate eluted withhexane and ethyl acetate (1/1) to yieldN′-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionyl]-hydrazinecarboxylicacid tert-butyl ester (40.1 mg, 94%). MS [M+H]⁺: 619.0; t_(R)=2.40 min.(method 1)

Step 31B: 4-Chlor3-(4-cyano-6-trifluoromethyl-pardon-3-yl)-N-methyl-N-{2-[2-(5-ox-45-dihydro-[1,3,4]oxadiazol-2-yl)-ethoxy]-phenyl}-benzamide

N′-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionyl]-hydrazinecarboxylicacid tert-butyl ester (40.1 mg, 0.065 mmol) was stirred in 4N HCl indioxane (5 mL) for 2 hrs and was concentrated. The residue was suspendedin toluene (5 mL) containing DIPEA (25.2 mg, 0.19 mmol). Phosgene (20%in toluene, 8.2 μL, 0.077 mmol) was added and the mixture was stirred atrt for 24 hrs. The mixture was concentrated and purified via reversephase preparative LCMS to give4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethoxy]-phenyl}-benzamide31-1 (17 mg). MS [M+H]⁺: 544.1; t_(R)=5.11 min. (method 3)

Example 32 2-Chloro-5-fluoro-quinoline-3-carbonitrile

Step 32A: (2-Amino-6-fluoro-phenyl)-methanol

LAH (987 mg, 26 mmol) was added slowly to a solution of2-amino-6-fluoro-benzoic acid (2.69 g, 17.3 mmol) in dry THF (20 mL) at0° C. The mixture was stirred at room temperature for approximately 1 hrand cooled to 0° C. again. Na₂SO₄10H₂O (10 g) was added slowly withstirring for 20 minutes. The mixture was filtered, the solid was washedwith THF. The solution was concentrated to yield a yellow solid as(2-amino-6-fluoro-phenyl)-methanol (2.49 g). MS [M-OH]⁺: 124.1;t_(R)=0.57 min. (method 1)

Step 32B: 2-Amino-6-fluoro-benzaldehyde

To (2-amino-6-fluoro-phenyl)-methanol (2.49 g, 17.3 mmol) indichloromethane (30 mL) was added MnO₂ (3.01 g, 34.7 mmol, activated).The mixture was refluxed for 3 hrs and then filtered over celite. Themixture was concentrated and purified via silica gel flashchromatography (eluting with 30% ethyl acetate in hexane) to give2-amino-6-fluoro-benzaldehyde as a yellow solid (1.23 g). t_(R)=2.20min. (method 1)

Step 32C: 5-Fluoro-2-oxo-1,2-dihydro-quinoline-3-carbonitrile

To a solution of MeOH (60 mL) containing 2-amino-6-fluoro-benzaldehyde(1.19 g, 8.6 mmol) and methyl cyanoacetate (0.91 mL, 10.3 mmol) wasadded sodium methoxide (2.93 mL, 12.8 mmol, 25% in MeOH). The mixturewas stirred at rt for 16 hrs. The resulting yellow precipitates werefiltered, washed with MeOH and then stirred in 1N HCl (75 mL) for 2 hrsat rt. The solid was filtered, washed with water and dried in vacuo toyield 5-fluoro-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (1.2 g) as awhite solid. MS [M+H]⁺: 189.1; t_(R)=2.00 min. (method 1)

Step 32D: 2-Chloro-5-fluoro-quinoline-3-carbonitrile

5-Fluoro-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (0.80 g, 4.3 mmol)was heated in POCl₃ (10 mL) for 3 hrs. The mixture was concentrated andpartitioned in ethyl acetate and water. The organic layer was separated,washed with NaHCO₃, dried and concentrated. The residue was crystallizedfrom a mixture of hexane and ethyl acetate to give2-chloro-5-fluoro-quinoline-3-carbonitrile 32-1 as a white solid (0.83g). ¹HNMR (CDCl₃), δ, 8.82 (1H, s), 7.83-7.92 (2H, m), 7.33-7.41 (1H,m).

The following compounds were prepared according to the proceduredescribed above.

MS t_(R) HPLC Ex. (M + H)⁺ (min) Method 32-12-Chloro-5-fluoro-quinoline-3- 207.0 2.40 1 carbonitrile 32-22-Chloro-8-fluoro-quinoline-3- 207.2 2.38 1 carbonitrile 32-32-Chloro-5,6,7,8-tetrafluoro- — 2.56 1 quinoline-3-carbonitrile

Example 334-(2-{[4-Chloro-3-(3-cyano-5-fluoro-quinolin-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricAcid

Step 33A: 3-Bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide(Alternative Synthesis to Step 3B)

3-Bromo-4-chloro-benzoyl chloride (Step 2A, 106.9 mmol) in acetonitrile(300 mL) was added dropwise over 30 minutes to a vigorously stirringsolution of 2-methylamino-phenol (15.1 g, 122.9 mmol) and NaHCO₃ (18.0g, 213.7 mmol) in acetonitrile (200 mL) and water (200 mL). The mixturewas stirred for additional 1 h and then concentrated to removeacetonitrile. The solid was filtered, washed with HCl (1N, 600 mL) andwater (500 mL), and dried. The solid was dissolved in dichloromethane(500 mL) and n-butylamine (20 mL) was added. The mixture was stirred atrt for 16 hrs and concentrated. The residue was partially purified viasilica gel flash chromatography (eluting with 20% to 35% ethyl acetatein hexane) and then crystallized from hexane/ethyl acetate (75/25) togive 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (20.5 g)as a white solid. MS [M+H]⁺: 339.7/341.8; t_(R)=2.19 min. (method 1)

Step 33B:4-{2-[(3-Bromo-4-chloro-benzoyl)-methyl-amino]-phenoxy}-butyric AcidTert-Butyl Ester

4-{2-[(3-Bromo-4-chloro-benzoyl)-methyl-amino]-phenoxy}-butyric acidtert-butyl ester (6.24 g) was similarly prepared according to Step 3C asa light yellow solid from3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (7.9 g, 23.2mmol). MS [M-tert-but]⁺: 426.0/428.0; t_(R)=2.69 min. (method 1)

Step 33C:4-(2-{[4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricAcid Tert-Butyl Ester

4-(2-{[4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricacid tert-butyl ester (5.36 g) was similarly prepared according to Step2D from 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenoxy}-butyricacid tert-butyl ester (6.23 g, 12.9 mmol). MS [M+H]⁺: 530.2; t_(R)=2.72min. (method 1)

Step 33D:4-(2-{[4-Chloro-3-(3-cyano-5-fluoro-quinolin-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricAcid Tert-Butyl Ester

4-(2-{[4-Chloro-3-(3-cyano-5-fluoro-quinolin-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricacid tert-butyl ester (80.2 mg) was similarly prepared according to Step15D from 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenoxy}-butyricacid tert-butyl ester (106.4 mg, 0.2 mmol) and2-chloro-5-fluoro-quinoline-3-carbonitrile 32-1 (41.5 mg, 0.2 mmol). MS[M+H]⁺: 574.3; t_(R)=2.97 min. (method 1)

Step 33E:4-(2-{[4-Chloro-3-(3-cyano-5-fluoro-quinolin-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricAcid

4-(2-{[4-Chloro-3-(3-cyano-5-fluoro-quinolin-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricacid tert-butyl ester (80.2 mg) was stirred in 50% trifluroacetic acidin dichloromethane (2 mL) for 2 hrs and purified via reverse phasepreparative LCMS to afford4-(2-{[4-chloro-3-(3-cyano-5-fluoro-quinolin-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyricacid 33-1 (22.9 mg). MS [M+H]⁺: 518.4; t_(R)=3.47 min. (method 3)

The following compounds were prepared according to the proceduredescribed above

HPLC Ex. R₄ MS (M + H)⁺ t_(R) (min) Method 33-1 5-fluoro 518.4 3.47 333-2 8-fluoro 518.3 3.41 3 33-3 5,6,7,8-tetrafluoro 572.4 3.72 3

Example 344-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]phenoxy}-butyricAcid

Step 34A: 5-Bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoicAcid 3-tert-butoxycarbonyl-propyl Ester

A mixture of 5-bromo-4-chloro-2-hydroxy-benzoic acid (5 g, 19.9 mmol),4-bromo-butyric acid tert-butyl ester (13.2 g, 59.7 mmol) and K₂CO₃(11.1 g, 79.6 mmol) in DMF (100 mL) was heated at 80° C. for 2 days. Thesolid was filtered off. The solution was concentrated and purified viasilica gel flash chromatography (eluting with 20% ethyl acetate inhexane) to give5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid3-tert-butoxycarbonyl-propyl ester (8.2 g). MS [M-iso-butene+H]⁺: 480.9;t_(R)=3.32 min. (method 1)

Step 34B: 5-Bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoicAcid

A mixture of 5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoicacid 3-tert-butoxycarbonyl-propyl ester (8.2 g, 15.3 mmol) and LiOH(19.1 mL, 4 N, 76.6 mmol) in THF (150 mL) was stirred at rt for 16 hrs.The mixture was acidified by saturated NaHSO₄ (50 mL) and extracted withethyl acetate. The ethyl acetate layer was dried over Na₂SO₄, filteredand concentrated. The residue was purified via silica gel flashchromatography (eluting with 50% ethyl acetate in hexane), followed bycrystallization in hexane/ethyl acetate (10/1) to afford5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid as whitecrystals (2.5 g). MS [M-(iso-butene+OH)]⁺: 320.8; t_(R)=2.38 min.(method 1)

Step 34C: 5-Bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoicAcid 2-trimethylsilanyl-ethyl Ester

To a stirring dichloromethane solution (40 mL) containing5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid (2.3 g,5.9 mmol) and 2-(trimethylsilyl)-ethanol (1.8 g, 8.9 mmol),dicyclohexyl-carbodiimide (1.83 g, 8.9 mmol) and DMAP (108 mg, 0.9 mmol)were added. The mixture was stirred at rt for 16 hrs and wasconcentrated. The residue was purified via silica gel flashchromatography (eluting with 20% ethyl acetate in hexane) to afford5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid2-trimethylsilanyl-ethyl ester (3.2 g). MS ion (APCI): 482.0, 441.0,410.9. t_(R)=3.61 min (method 1)

Step 34D:2-(3-tert-Butoxycarbonyl-propoxy)-4-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoicAcid-2-trimethylsilanyl-ethyl Ester

2-(3-tert-Butoxycarbonyl-propoxy)-4-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-benzoicacid-2-trimethylsilanyl-ethyl ester (2.7 g) was similarly preparedaccording to Step 2D from5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid2-trimethylsilanyl-ethyl ester (3.2 g). MS ion (APCI): 513.2, 459.1;t_(R)=3.62 min. (method 1)

Step 34E:2-(3-tert-Butoxycarbonyl-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoicAcid 2-trimethylsilanyl-ethyl Ester

2-(3-tert-Butoxycarbonyl-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoicacid 2-trimethylsilanyl-ethyl ester (1.3 g) was similarly preparedaccording to Step 2E.1 or Step 3E from5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid2-trimethylsilanyl-ethyl ester (2.2 g). MS ion (APCI): 501.1; t_(R)=3.59min (method 1)

Step 34F:2-(3-tert-Butoxycarbonyl-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoicAcid

A mixture of2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoicacid 2-trimethylsilanyl-ethyl ester (1.3 g, 2.2 mmol) andtetrabutyl-ammonium fluoride (6.6 mL, 6.6 mmol, 1 M in THF) in THF (20mL) was stirred at rt for 30 minutes. The mixture was then concentratedand diluted with ether. The ether layer was washed with water, dried andconcentrated to yield2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoicacid (0.8 g). MS [M+H]⁺: 485.1; t_(R)=2.96 min (method 1)

Step 34G:4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyricAcid

A mixture of2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoicacid (30 mg, 0.06 mmol), 2-methoxy-N-methylaniline (9.4 mg, 0.07 mmol),triethylamine (12.5 mg, 0.12 mmol) and2-(7-aza-1H-benzotriazole-1-yl)-1,3,3-tetramethyluroniumhexafluorophosphate (HATU, 35 mg, 0.09 mmL) in dichloromethane (1 mL)containing DMF (0.1 mL) was stirred at rt for 16 hrs. The mixture wasthen partitioned in water and dichloromethane. The organic layer waswashed with water, dried and concentrated to yield a crude4-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyricacid t-butyl ester.

Alternatively, 2-methoxyaniline was used for amide formation, followedby performing N-methylation according to Step 2C to afford the sameintermediate.

The above crude material was stirred in 50% trifluoroacetic acid indichloromethane (1 mL) for 2 hrs and then purified via reverse phasepreparative LCMS to afford4-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyricacid 34-1 (4.5 mg).

The following compounds were prepared according to the proceduredescribed above:

MS t_(R) HPLC Ex. R_(2a) (M + H)⁺ (min) Method 34-1 2-methoxy-phenyl548.3 3.91 3 34-2 4-chloro-2-methoxy-phenyl 582.3 4.06 3 34-32-trifluoromethoxy-phenyl 602.3 4.08 3 34-4 4-fluoro-2-methoxy-phenyl566.3 3.70 3 34-5 2-methoxymethyl-phenyl 562.2 3.49 3 34-63-chloro-2-methoxy-phenyl 582.0 8.20 2 34-7 5-chloro-2-methoxy-phenyl582.0 8.10 2 34-8 phenyl 518.3 3.81 3 34-94-chloro-2-methoxymethyl-phenyl 596.1 3.82 3 34-102-methoxycarbonyl-phenyl 576.2 3.35 3 34-11 3-fluoro-2-methoxy-phenyl566.8 3.70 3 34-12 5-methyl-2-methoxy-phenyl 562.4 3.74 3 34-132,5-dimethoxy-phenyl 577.6 3.53 3 34-14 2,4-dimethoxy-phenyl 577.6 3.673 34-15 2-oxazol-5-yl-phenyl 585.7 3.37 3 34-16 2-furan-2-yl-phenyl584.4 3.83 3 34-17 benzyl 523.3 3.90 3 34-18 2-pyridyl 519.3 3.51 334-19 6-methoxy-pyridin-2-yl 549.2 3.43 3 34-20 3-methyl-pyridin-2-yl532.8 3.39 3 34-21 6-methyl-pyridin-2-yl 532.8 3.12 3 34-22 methyl 455.72.95 3 34-23 3-methyl-butyl 512.0 3.69 3 34-24 2-methoxy-ethyl 500.13.09 3 34-25 cyclopropylmethyl 496.0 3.47 3 34-266-fluoro-2-methoxy-phenyl 566.1 3.73 3

Example 354-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-2-[3-(1H-tetrazol-5-yl)-propoxy]-benzamide

Step 35A:5-Bromo-4-chloro-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide

To a stirring dichloromethane (40 mL) solution containing5-bromo-4-chloro-2-hydroxybenzoic acid (2.0 g, 8.0 mmol), were addedtriethylamine (2.2 mL, 16.0 mmol), HATU (4.5 g, 12 mmol) and2-methoxyl-N-methylaniline (1.19 g, 8.7 mmol). The mixture was stirredat rt for 16 hrs and water was added. The organic layer was separated,washed with NaHCO₃, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified via silica gel flash column chromatography elutingwith 20% ethyl acetate in hexane to afford5-bromo-4-chloro-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide (300mg). MS [M+H]+: 371.9; t_(R)=2.60 min (method 1)

Alternatively, a mixture of 5-bromo-4-chloro-2-hydroxybenzoic acid (5 g,19.9 mmol), 2-methoxy-N-methyaniline (3.13 g, 22.9 mmol) and P₂O₅ (5.36g, 37.8 mmol) in anhydrous xylene was heated at 60° C. for 2 hrs andthen refluxed for 17 hrs. The mixture was concentrated and purified viasilica gel flash column chromatography eluted with ethyl acetate inhexane (20%) to give5-bromo-4-chloro-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide (3.3g).

Step 35B:5-Bromo-4-chloro-2-(3-cyano-propoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide

To a stirring DMF solution (6 mL) containing5-bromo-4-chloro-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide (300mg, 0.81 mmol) was added 4-bromobutyronitrile (0.096 mL, 0.97 mmol) andK₂CO₃ (223 mg, 1.62 mmol). The mixture was heated at 50° C. for 8 hrs.Additional 0.5 eq. of 4-bromobutyronitrile and 0.5 eq of K₂CO₃ wereadded and the mixture was heated for another 8 hrs. The mixture wasdiluted with dichloromethane, washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified via silica gel flashcolumn chromatography to afford5-bromo-4-chloro-2-(3-cyano-propoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide(241 mg). MS [M+H]⁺: 439.1; t_(R)=2.62 min (method 1)

Step 35C:5-Bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-2-[3-(1H-tetrazol-5-yl)-propoxy]-benzamide

5-Bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-2-[3-(1H-tetrazol-5-yl)-propoxy]-benzamide(226 mg) was similarly prepared according to Step 28B from thecorresponding5-bromo-4-chloro-2-(3-cyano-propoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide(241 mg). MS [M+H]⁺: 482.1; t_(R)=2.48 min (method 1)

Steps 35D:4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-2-[3-(1H-tetrazol-5-yl)-propoxy]-benzamide

4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-2-[3-(1H-tetrazol-5-yl)-propoxy]-benzamide35-1 was prepared from5-bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-2-[3-(1H-tetrazol-5-yl)-propoxy]-benzamidevia stepwise reactions of Steps 28C, D, E and F. MS [M+H]⁺: 572.2;t_(R)=7.48 min (method 2)

Example 36 2,2-Dimethyl-propionic acid3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionyloxymethylEster

Step 36A: 2,2-Dimethyl-propionic Acid3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionyloxymethylEster

A mixture of3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicacid 11-4 (500 mg, 0.95 mmol), chloromethyl pivalate (276.4 j L, 1.9mmol), triethylamine (399 μL, 2.85 mmol), NaI (142.5 mg, 0.95 mmol) inDMF (5 mL) was stirred at rt for 2 days. Ethyl acetate was added and themixture was washed with water and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified via silica gel flash columnchromatography eluting with 20% ethyl acetate in hexane to afford2,2-dimethyl-propionic acid3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionyloxymethylester 36-1 as a white foam. MS [M+H]⁺: 618.2; t_(R)=32.7 min (method 5).

Similarly,4-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyricacid 2,2-dimethyl-propionyloxymethyl ester 36-2 was prepared from 34-1.MS [M+H]⁺: 662.2; t_(R)=6.87 min (method 3)

Example 373-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicAcid 1-cyclohexyloxycarbonyloxy-ethyl Ester

Step 37A:3-(2-{4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl-methyl-amino}-phenoxy)-propionicAcid 1-cyclohexyloxycarbonyloxy-ethyl Ester

A mixture of3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicacid 11-4 (500 mg, 0.95 mmol), carbonic acid 1-chloroethyl cyclohexylester (393 mg, 1.9 mmol), triethylamine (399 μL, 2.85 mmol), and NaI(142.5 mg, 0.95 mmol) in DMF (5 mL) were stirred at 60° C. for 1 day.Ethyl acetate was added and the mixture was washed with water and brine,dried over MgSO₄, filtered and concentrated. The residue was purifiedvia silica gel flash column chromatography eluting with 20% ethylacetate in hexane to afford3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicacid 1-cyclohexyloxycarbonyloxy-ethyl ester 37-1. MS [M+H]⁺: 674.2;t_(R)=35.7 min (method 5).

Similarly,3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicacid 1-isopropoxycarbonyloxy-ethyl ester 37-2 was prepared from 11-4 andcarbonic acid 1-chloroethyl isopropyl ester. MS [M+H]⁺: 634.2;t_(R)=32.5 min (method 5).

Similarly,4-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyricacid 1-cyclohexyloxycarbonyloxy-ethyl ester 37-3 was prepared from 34-1.MS [M+H]⁺: 718.3; t_(R)=7.23 min (method 3).

Similarly,4-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyricacid 1-isopropoxycarbonyloxy-ethyl ester 37-4 was prepared from 34-1. MS[M+H]⁺: 678.3; t_(R)=6.73 min (method 3).

Example 384-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-(2-methoxy-phenyl)-N-methyl-benzamide

Step 38A:4-Chloro-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoicAcid Methyl Ester

4-Chloro-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoicacid methyl ester (9.8 g) was prepared from5-bromo-4-chloro-2-methoxybenzoic acid methyl ester (10.0 g) accordingto the procedure of Step 2D. MS [M+H]⁺: 327.1; t_(R)=2.96 min (method 1)

Step 38B:4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoicAcid Methyl Ester

4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoicacid methyl ester (5.5 g) was prepared according to Step 2E.1 from4-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoicacid methyl ester (9.8 g) and5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1 (7.6 g). MS [M+H]⁺:371.0; t_(R)=2.83 min (method 1)

Steps 38C:4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoicAcid

A mixture of4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoicacid methyl ester (1.2 g, 3.2 mmol) and trimethyltin hydroxide (1.75 g,9.7 mmol) in 1,2-dichloroethane (50 mL) was heated to 80° C. in a sealedtube for 4 hrs. Additional 5.0 eq. of trimethyltin hydroxide was addedand the mixture was heated for total of 48 hrs. The mixture was thencooled to rt, quenched with HCl (2N, 40 mL) and diluted with1,2-dichloroethane. The organic layer was separated, dried over Na₂SO₄,filtered and concentrated. The residue was purified via silica gel flashcolumn chromatography eluting with dichloromethane:methanol (9:1) toafford4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoicacid (723 mg). NMR (CDCl₃), δ, 8.82 (1H, s), 7.94 (1H, s), 7.81 (1H, s),7.20 (1H, s), 3.90 (3H, s).

Step 38C.1:4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoicAcid (Alternative Synthesis)

N₂ was bubbled through a solution of THF (8 mL) and water (2 mL)containing 5-carboxy-2-chloro-4-methoxy-phenylboronic acid (460.8 mg,2.0 mmol) and 5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1 (478 mg,1.9 mmol) for 10 minutes. K₃PO₄ (1.2 g, 5.7 mmol), t-Bu₃P.HBF₄ (82.7 mg,0.28 mmol), and Pd₂dba₃ (91.0 mg, 0.1 mmol) were added under N₂atmosphere. The mixture was sealed, stirred at rt for 3 hrs, and dilutedwith ethyl acetate. The organic layer was separated, washed with brine,dried over MgSO₄, filtered and concentrated. The residue was purifiedvia silica gel flash column chromatography eluting with 10% MeOH indichloromethane to give4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoicacid (301 mg).

Similarly, 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoicacid was prepared according to the above procedure from5-carboxy-2-chloro-phenylboronic acid and5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1.

Step 38D:4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-(2-methoxy-phenyl)-N-methyl-benzamide

To a mixture of 2-methoxyl-N-methylaniline (27.7 mg, 0.2 mmol) and Et₃AI(196 μL, 1.9 M in toluene, 0.2 mmol) in 1,2-dichloroethane (1 mL) whichwas preheated at 50° C. for 10 min under N₂ atmosphere, was added4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoicacid methyl ester (50 mg, 0.14 mmol). The mixture was sealed in N₂atmosphere and heated at 80° C. for 16 hrs. Upon cooling to rt, themixture was quenched with 2 N HCl (5 mL) and diluted with1,2-dichloroethane. The organic layer was separated and concentrated.The residue was purified via reverse phase preparative LCMS to yield4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-(2-methoxy-phenyl)-N-methyl-benzamide38-1 (4.9 mg). MS [M+H]⁺; 475.9; t_(R)=5.91 min (method 3)

Example 394-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-N-methyl-benzamide

Step 39A: 4-Chloro-2-methoxy-5-(6-trifluoromethyl-pyridin-3-yl)-benzoylChloride

To a stirring dichloromethane solution (5 mL) containing4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoicacid (Step 38C or 38C.1, 436 mg, 1.2 mmol), was added 2 drops of DMF andthen oxalyl chloride (128 μL, 1.5 mmol) under N₂. The mixture wasstirred at rt for 2 hrs and concentrated to yield4-chloro-2-methoxy-5-(6-trifluoromethyl-pyridin-3-yl)-benzoyl chlorideas a solid, which was used in the next step without furtherpurification.

Similarly, 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoylchloride was prepared from4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoic acid (Step38C.1).

Step 39B:4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-benzamide

To 4-chloro-2-methoxy-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoylchloride (70 mg, 0.19 mmol) in DCM (0.5 mL) were added triethylamine (39μL, 0.28 mmmol) and 2,6-dimethylaniline (28 μL, 0.22 mmol). The mixturewas stirred at rt for 12 hrs and was purified via a prep TLC plateeluting with ethyl acetate in hexane (30%) to give4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-benzamide(55.0 mg). MS [M+H]⁺ 460.2; t_(R)=2.85 min (method 1)

Step 39C:4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-N-methyl-benzamide

To4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-benzamide(55.0 mg, 0.12 mmol) in dry DMF (0.5 mL) was added NaH (9.6 mg, 0.32mmol) and iodomethane (0.15 mL, 0.24 mmol). The mixture was stirred atrt overnight, quenched with 0.5 mL of MeOH and 2 drops oftrifluoroacetic acid, and purified via reverse phase preparative LCMS toyield4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-N-methyl-benzamide39-1 (8.3 mg). MS [M+H]⁺ 471.1; t_(R)=6.25 min (method 3)

The following compounds were prepared according to the proceduredescribed above, where in some cases, Step 39C was not necessary due toavailability of the N-methyl amine.

MS t_(R) HPLC Ex. R (M + H)⁺ (min) Method 39-1 2,6-dimethyl-phenyl 474.16.25 3 39-2 2-methoxycarbonyl-phenyl 504.2 5.82 3 39-32,6-dimethoxy-phenyl 506.1 5.81 3 39-4 2-fluoro-6-methoxy-phenyl 494.26.03 3 39-5 5-fluoro-2-methoxy-phenyl 494.2 6.02 3 39-62,6-difluoro-phenyl 482.2 6.10 3 39-7 phenyl 446.1 5.91 3 39-85-chloro-2-methoxycarbonyl-phenyl- 538.1 6.24 3 39-92-(2,2,2-trifluoro-ethoxy)-phenyl 544.2 6.18 3 39-102-methoxy-6-methyl-phenyl 490.2 6.10 3 39-11 5-fluoro-2-methyl-phenyl478.1 6.17 3 39-12 2-oxazol-5-yl-phenyl 513.1 5.53 3 39-133-methoxy-pyridin-2-yl 477.1 6.85 2 39-14 Pyridin-2-yl 447.2 5.33 339-15 benzyl 460.3 6.11 3 39-16 2-fluoro-benzyl 478.3 6.17 3 39-172-methoxy-benzyl 490.3 6.20 3 39-18 3-methoxy-benzyl 490.3 6.11 3 39-192-(2-dimethylamino-ethoxy)-benzyl 547.3 6.02 3 39-204-methoxy-pyridin-3-yl 477.3 5.01 3 39-21 3-methyl-pyridin-2-yl 461.25.29 3 39-22 benzothiazol-2-yl 503.1 6.39 3 39-23 6-methoxy-pyridin-2-yl477.1 5.98 3

Example 404-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-ethoxy]-phenyl}benzamide

Step 40A:4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-ethoxy]-phenyl}-benzamide

To a stirring solution of dichloromethane (5.0 mL) containing4-chloro-3-(4-cyano-6-trifluoromethylpyridin3-yl)-N-[2-(3-hydroxy-propoxy)-phenyl]-N-methyl-benzamide9-4 (304.0 mg, 0.62 mmol), was added Dess-Martin periodinane (263.2 mg,0.62 mmol). The mixture was stirred at rt for 2 hrs. The solid wasfiltered off and resulting solution was concentrated to give thealdehyde intermediate which was redissolved in t-BuOH (9.0 mL), followedby addition of water (3 mL) and NH₂NH₂ (20.5 μL, 0.65 mmol) at 0°−5° C.After additional stirring at rt for 30 min, the mixture was treated withNaOCN (64.5 mg, 0.99 mmol) and acetic acid (71.7 μL, 1.24 mmol) at 10°C. and stirred for another 2 hrs at the same temperature. A 10% bleachsolution (0.37 mL, 0.62 mmol) was added and the mixture was stirred atrt for 2 days. The mixture was diluted with water, extracted with ethylacetate and purified by prep. TLC plate eluting with 5% MeOH indichloromethane to yield4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-ethoxy]-phenyl}-benzamide40-1 (63.4 mg). MS [M+H]⁺ 543.2; t_(R)=6.46 min (method 2).

Example 414-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-{2-[2-(3-methylsulfonyl-ureido)-ethoxy]-phenyl}-N-methyl-benzamide

Step 41A:4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-{2-[2-(3-methylsulfonyl-ureido)-ethoxy]-phenyl}-N-methyl-benzamide

To a mixture of3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicacid 11-4 (272.9 mg, 0.54 mmol), CH₃SO₂NH₂ (51.5 mg, 0.54 mmol) andK₂CO₃ (224.4 mg, 1.63 mmol) in dioxane (4.0 mL), was addeddiphenylphosphoryl azide (141 μL, 0.65 mmol). The mixture was heated at85° C. for 3 hrs, diluted with water, acidified to pH 3 by NaHSO₄aqueous solution, then extracted with ethyl acetate. The organicsolution was then dried, concentrated and purified by prep. TLC plateeluting with 4% MeOH in dichloromethane to afford4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-{2-[2-(3-methylsulfonyl-ureido)-ethoxy]-phenyl}-N-methyl-benzamide41-1 (20.5 mg). MS [M+H]⁺ 596.3; t_(R)=7.29 min (method 2).

Example 424-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-2-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-benzamide

Step 42A:4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-2-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-benzamide

4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-2-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-benzamide42-1 was prepared according to Step 21A to Step 21G of Example 21. MS:573.3 (M+H)⁺, t_(R)=5.36 min (method 3).

The follow compounds were prepared similarly:

MS (M + t_(R) HPLC Ex. -Alkyl- —R₅ H)⁺ (min) Method 42-1 —CH₂CH₂— 2-oxo-573.3 5.36 3 pyrrolidin- 1-yl 42-2 —CH₂CH₂— Morpholin-4-yl 575.1 9.00 342-3 —CH₂CH₂— Imidazol-1-yl 556.0 5.25 3 42-4 —CH₂CH₂— Pyridin-2-yl568.7 5.84 3 42-5 —CH₂CH₂— 4-Methyl-4,5- 587.4 5.94 3 dihydrothiazol-5-yl 42-6 —CH₂CH₂CH₂— Pyridin-2-yl 581.6 8.38 3 42-7 —CH₂CH₂CH₂—1H-pyrazol- 570.2 5.56 3 4-yl 42-8 —CH₂CH₂O— Pyridin-2-yl 583.2 6.32 342-9 —CH₂CH₂CH₂— Pyridin-4-yl 581.5 5.96 3 42-10 —CH₂CH₂CH₂— Pyrrol-1-yl569.4 6.92 3 42-11 —CH₂CH₂CH₂— Imidazol-1-yl 570.2 5.61 3 42-12—CH₂CH₂CH₂— pyrazol-1-yl 570.2 6.08 3 42-13 —CH₂CH₂CH₂— 1,2,4-triazol-571.2 5.65 3 1-yl 42-14 —CH₂CH₂CH₂— 1-methyl-1H- 584.3 5.99 3pyrazol-3-yl 42-15 —CH₂CH₂CH₂O— Pyridin-2-yl 597.1 8.67 2 42-16 —CH₂CH₂—NH₂ 505.3 5.77 3 42-17 —CH₂CH₂— NHMe 519.3 5.58 3 42-18 —CH₂CH₂(NH₂)CH₂—OH 535.3 5.38 3

Example 434-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyricAcid Ethyl Ester

Step 43A:4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyricAcid Ethyl Ester

To4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyricacid in ethanol (1 mL), 10 drops of SOCl₂ were added. The mixture wasstirred at rt for 24 hrs. The crude was purified via reverse phasepreparative LCMS to afford4-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyricacid ethyl ester 43-1 (12.2 mg). MS: [M+H]⁺ 576.3; t_(R)=6.33 min(method 3).

Example 44{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-aceticAcid

Step 44A:5-Bromo-4-chloro-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-benzamide

2-Methoxy-N-methylaniline (7.4 g, 53.8 mmol) and triethylamine (10.9 g,107.7 mmol) were added to 5-bromo-4-chloro-2-fluoro-benzoyl chloride(Step 21D, 11.7 g, 43.1 mmol) in DCM (200 mL) at 0° C. The mixture wasthen allowed to warm to rt and concentrated. The mixture was partitionedin water and ethyl acetate. The organic layer was separated, washed withNaHSO₄ solution, water and brine, and was dried. After filtration andconcentration, the residue was purified via silica gel flash columnchromatography eluting with ethyl acetate in hexane (50%) to give5-bromo-4-chloro-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-benzamide (12.5g). MS: [M+H]⁺ 374.0/372.0; t_(R)=2.70 min (method 1)

Step 44B:2-{4-Bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-malonicAcid Dimethyl Ester

t-BuOK (7.23 g, 64.5 mmol) was added to dimethyl malonate (8.52 g, 7.3mL, 64.5 mmol) in dry DMF (60 mL). The mixture was heated at 90° C. for10 min to form the corresponding sodium salt which was added to a DMF(40 mL) solution containing5-bromo-4-chloro-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-benzamide (3.0g, 8.1 mmol) under N₂. The mixture was heated with stirring at 80° C.for 16 hrs, diluted with ethyl acetate, washed with water and brine, anddried over MgSO₄. The filtrate was concentrated and subject to silicagel column chromatography eluting with ethyl acetate in hexane (20%) toyield2-{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-malonicacid dimethyl ester (1.4 g) as a light yellow oil. MS: [M+H]⁺487.9/486.0; t_(R)=2.82 min (method 1)

Step 44C:2-{4-Bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-acetic

A mixture of2-{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-malonicacid dimethyl ester (1.4 g, 2.8 mmol) and LiOH.H₂O (0.7 g, 16.7 mmol)was stirred at 60° C. in a mixture of THF (20 mL) and water (2 mL) for24 hrs, then acidified by 1N HCl to pH 4. The mixture was extracted withethyl acetate. The ethyl acetate layer was then washed with water andbrine, and was dried over MgSO₄. The filtrate was then concentrated andpurified by silica gel flash column chromatography eluting with 10% MeOHin DCM to yield2-{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-aceticacid (427 mg). MS: [M+H]⁺ 413.9/412.0; t_(R)=2.60 min (method 1)

Step 44D:{4-Bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-aceticAcid 2-trimethylsilanyl-ethyl Ester

To a solution of DCM (10 mL) containing2-{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-aceticacid (427 mg, 1.0 mmol) and 2-trimethylsilylethanol (183 mg, 1.5 mmol),were added DMAP (18.9 mg, 0.15 mmol) and DCC (320 mg, 1.5 mmol). Themixture was stirred at rt for 24 hrs, concentrated, and then directlypurified via silica gel column chromatography eluting with ethyl acetatein hexane (20%) to yield{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-aceticacid 2-trimethylsilanyl-ethyl ester (520 mg). MS: (M-CH₂CH₂)⁺487.9/486.0; t_(R)=3.34 min (method 1).

Step 44E:[5-Chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic Acid 2-trimethylsilanyl-ethylEster

[5-Chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenyl]-aceticacid 2-trimethylsilanyl-ethyl ester (570 mg) was obtained from thecorresponding{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-aceticacid 2-trimethylsilanyl-ethyl ester (520 mg) according to Step 2D ofExample 2. MS: [M+H]⁺ 560.2; t_(R)=3.45 min (method 1).

Step 44F:{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-aceticAcid

{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-aceticacid 2-trimethylsilanyl-ethyl ester (615 mg) was obtained from[5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenyl]-aceticacid 2-trimethylsilanyl-ethyl ester (570 mg) and5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1 (305 mg) according toStep 38C.1 of Example 38. The crude was redissolved in THF (10 mL) andtetrabutylammonium fluoride (1M in THF, 3 mL) was added. The mixture wasstirred at rt for 1 hr, acidified by 1N HCl (2 mL) and extracted withether. The ether layer was then washed with water, brine and dried overMgSO₄. The filtrate was concentrated and purified via silica gel flashcolumn chromatography eluting with 10% MeOH in DCM to yield{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-aceticacid 44-1 (246 mg). MS: [M+H]⁺ 504.0; t_(R)=7.54 min (method 2).

Example 454-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-benzamide

Steps 45A: 3-(2-Methylamino-phenoxy)-propionitrile

A solution of 2-methylaminophenol (0.74 g, 6.0 mmol), Triton B (60 ILL,40% in water) and acrylonitrile (4.0 mL, 60 mmol) was refluxed for 16hrs. The mixture was diluted with ethyl acetate. The organic layer wasthen washed with water and brine, and was dried over MgSO₄. Afterfiltration and concentration, the residue was purified via silica gelflash column chromatography eluting with 20% ethyl acetate in hexane togive 3-(2-methylamino-phenoxy)-propionitrile (4.0 g) as a brown oil.[M+H]⁺ 177.1; t_(R)=0.715 min (method 1).

Steps 45B: Methyl-{2-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-amine

To a solution of 3-(2-methylamino-phenoxy)-propionitrile (1.55 g, 8.8mmol) and azidotributyltin (3.6 mL, 13.2 mmol) in toluene (30 mL) wasadded triethylaluminum (9.3 mL, 17.6 mmol, 1.9 M in toluene). Themixture was heated at 80° C. for 16 hrs. The mixture was diluted withwater (100 mL) and ethyl acetate (200 mL). The ethyl acetate layer wasseparated and removed. The resultingmethyl-{2-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-amine stayed in theaqueous solution and was used in the next step without purification.[M+H]+ 220.1; t_(R)=0.388 min (method 1).

Steps 45C:4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-benzamide

The stirring aqueous solution ofmethyl-{2-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-amine was basified withsat. NaHCO₃ and diluted with acetonitrile (40 mL).4-Chloro-5-(6-trifluoromethyl-pyridin-3-yl)-benzoyl chloride (Step 39A,2.9 g, 8.8 mmol) in acetonitrile (20 mL) was added dropwise. The mixturewas stirred for 2 hrs, acidified, and concentrated to removeacetonitrile. The concentrated mixture was extracted with ethyl acetate.The organic layer was then washed with water and brine, and was driedover MgSO₄. After filtration and concentration, the residue was purifiedvia silica gel flash column chromatography eluting with 2% MeOH in DCMand then further purified via silica gel flash column chromatographyeluting with 50% ethyl acetate in hexane to produce4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-benzamide45-1 (3.2 g). [M+H]⁺ 528.2; t_(R)=3.43 min (method 3).

Similarly,4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-methyl-N-{2-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-benzamide45-2 was prepared. [M+H]⁺ 558.1; t_(R)=7.82 min (method 2).

Example 464-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(3-isoxazol-4-yl-propoxy)-N-(2-methoxyphenyl)-N-methyl-benzamide

Step 46A:4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(3-isoxazol-4-yl-propoxy)-N-(2-methoxyphenyl)-N-methyl-benzamide

To a solution of4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide(30 mg, 0.065 mmol) in THF (700 ML), 3-isoxazol-4-yl-propan-1-ol (9 mg,0.071 mmol), triphenylphosphine (26 mg, 0.089 mmol) and DIAD (20 μL,0.098 mmol) were added. The mixture was stirred at rt overnight,concentrated, diluted with 1 mL MeOH and purified by prep HPLC to give4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(3-isoxazol-4-yl-propoxy)-N-(2-methoxyphenyl)-N-methyl-benzamide 46-1. MS: 571.2 (M+H)⁺, t_(R)=6.12 min(method 3).

The following compounds were prepared similarly.

MS t_(R) HPLC Ex. -Alkyl- —R₅ (M + H)⁺ (min) Method 46-1 —CH₂CH₂CH₂—isoxazol-4-yl 571.2 6.12 3 46-2 —CH₂CH₂— 2-methoxyphenyl 596.5 6.97 346-3 —CH₂CH₂— Pyrazin-2-yl 568.4 5.71 3 46-4 —CH₂CH₂CH₂— 1,3-dioxo-1,3-649.3 6.39 3 dihydro- isoindol-2-yl

Example 472-(2-Acetylamino-ethoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide

Step 47A:2-(2-Acetylamino-ethoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide

To a solution of2-(2-amino-ethoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide(30 mg, 0.06 mmol) in DCM (1 mL) acetic anhydride (11 μL, 0.12 mmol) andDIPEA (16 μL, 0.09 mmol) were added. The mixture was stirred at rtovernight, concentrated, diluted with 1 mL MeOH and purified bypreparative HPLC yielding2-(2-acetylamino-ethoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide.MS: 547.1 (M+H)⁺, t_(R)=7.48 min (method 2).

The following compounds were prepared similarly.

MS (M + t_(R) HPLC Ex. -Alkyl- —R₅ H)⁺ (min) Method 47-1 —CH₂CH₂——NHC(═O)CH₃ 547.1 7.48 2 47-2 —CH₂CH₂— —N(CH₃)C(═O)CH₃ 561.0 7.19 2 47-3—CH₂CH₂CH₂— —NHC(═O)CH₃ 561.1 7.28 2 47-4 —CH₂CH₂— —NHC(═O)CF₃ 601.18.54 2 47-5 —CH₂CH₂— —N(CH₃)C(═O)CF₃ 615.0 8.78 2

Example 484-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2-methanesulfonylamino-ethoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide

Step 48A:4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2-methanesulfonylamino-ethoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide

To a solution of2-(2-amino-ethoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide(30 mg, 0.06 mmol) in DCM (1 mL), methanesulfonylchloride (7 μL, 0.09mmol) and DIPEA (16 μL, 0.09 mmol) were added. The mixture was stirredat rt overnight, concentrated, diluted with 1 mL MeOH and purified byprep HPLC yielding4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2-methanesulfonylamino-ethoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide48-1. MS: 583.0 (M+H)⁺, t_(R)=7.61 min (method 2).

4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[2-(methanesulfonyl-methyl-amino)-ethoxy]-N-(2-methoxy-phenyl)-N-methyl-benzamide48-2 was prepared similarly. MS: 597.1 (M+H)⁺, t_(R)=7.91 min (method2).

Example 49(S)-1-(3-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-propyl)-pyrrolidine-2-carboxylicacid

Step 49A: (S)-1-(3-Hydroxy-propyl)-pyrrolidine-2-carboxylic AcidTert-Butyl Ester

To a solution of (S)-pyrrolidine-2-carboxylic acid tert-butyl ester (350mg, 2.04 mmol) in CH₃CN (5 mL), 3-bromo-propan-1-ol (268 μL, 3.06 mmol)and K₂CO₃ (844 mg, 6.12 mmol) were added. The mixture was heated at 85°C. overnight, concentrated and purified by silica gel columnchromatography (DCM/MeOH=95/5) to afford 444 mg(S)-1-(3-hydroxy-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester.MS: 230.2 (M+H)⁺, t_(R)=0.99 min (method 1).

Step 49B:(S)-1-(3-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-propyl)-pyrrolidine-2-carboxylicAcid

To4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamidealcohol (30 mg, 0.065 mmol) dissolved in THF (700 μL),(S)-1-(3-hydroxy-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester(18 mg, 0.078 mmol), triphenylphosphine (26 mg, 0.1 mmol) and DIAD (20μL, 0.1 mmol) were added. The mixture was stirred at rt overnight,concentrated, diluted with 1 mL MeOH and purified by prep HPLC. Theresulting(S)-1-(2-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-ethyl)-pyrrolidine-2-carboxylicacid tert-butyl ester was treated with 50% TFA in DCM (2 mL), stirred atrt for 4 hrs and concentrated yielding(S)-1-(3-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-propyl)-pyrrolidine-2-carboxylicacid 48-1. MS: 617.4 (M+H)⁺, t_(R)=4.44 min (method 3).

The following compounds were prepared similarly

MS (M + t_(R) HPLC Ex. -Alkyl- —R₅ H)⁺ (min) Method 49-1 —CH₂CH₂CH₂—(S)-pyrrolidin1-yl-2- 617.4 4.44 3 carboxylic acid 49-2 —CH₂CH₂—(R)-pyrrolidin1-yl-2- 603.4 3.85 3 carboxylic acid 49-3 —CH₂CH₂—(S)-pyrrolidin1-yl-2- 603.3 3.81 3 carboxylic acid 49-4 —CH₂CH₂CH₂—(R)-pyrrolidin1-yl-2- 617.4 4.39 3 carboxylic acid

Example 50(S)-1-[3-(2-{[4-Chloro-3-(4-cyan-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propyl]-pyrrolidine-2-carboxylicAcid

Step 50A:(S)-1-[3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propyl]-pyrrolidine-2-carboxylicacid

To4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide(30 mg, 0.069 mmol) dissolved in THF (700 μL),(S)-1-(3-hydroxy-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester(18 mg, 0.078 mmol), triphenylphosphine (26 mg, 0.1 mmol) and DIAD (20μL, 0.1 mmol) were added. The mixture was stirred at rt overnight,concentrated, diluted with 1 mL MeOH and purified by prep HPLC. Theresulting(S)-1-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propyl]-pyrrolidine-2-carboxylicacid tert-butyl ester was treated with 50% TFA in DCM (2 mL), stirred atrt for 4 hrs and concentrated yielding(S)-1-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propyl]-pyrrolidine-2-carboxylicacid 50-1. MS: 587.4 (M+H)⁺, t_(R)=4.34 min (method 3).

The following compounds were prepared similarly

MS (M + t_(R) HPLC Ex. -Alkyl- —R₅ H)⁺ (min) Method 50-1 —CH₂CH₂CH₂—(S)-pyrrolidin1-yl-2- 587.4 4.34 3 carboxylic acid 50-2 —CH₂CH₂—(R)-pyrrolidin1-yl-2- 573.1 5.92 2 carboxylic acid 50-3 —CH₂CH₂—(S)-pyrrolidin1-yl-2- 573.1 5.93 2 carboxylic acid 50-4 —CH₂CH₂CH₂—(R)-pyrrolidin1-yl-2- 587.4 4.33 3 carboxylic acid

Example 514-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(pyridin-2-yloxy)-ethoxy]-phenyl}-benzamide

Step 51A: Methanesulfonic acid 2-(pyridin-2-yloxy)-ethyl Ester

2-(Pyridin-2-yloxy)-ethanol (100 mg, 0.72 mmol) was dissolved in DCM (2mL) and MsCl (72 μL, 0.94 mmol) and DIPEA (192 μL, 1.08 mmol) wereadded. The mixture was stirred at rt overnight, diluted with EtOAc,washed with water, sat NaHCO₃ and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo to afford 114 mg methanesulfonic acid2-(pyridin-2-yloxy)-ethyl ester which was used without furtherpurification for the next step.

Step 51B:4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(pyridin-2-yloxy)-ethoxy]-phenyl}-benzamide

To4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide(50 mg, 0.12 mmol) dissolved in DMF (500 ML), methanesulfonic acid2-(pyridin-2-yloxy)-ethyl ester (30 mg, 0.14 mmol) and K₂CO₃ (50 mg,0.36 mmol) were added. The mixture was stirred at rt overnight thenheated at 40° C. for 1 h. After filtration and dilution with MeOH themixture was purified by prep HPLC yielding4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(pyridin-2-yloxy)-ethoxy]-phenyl}-benzamide51-1. MS: 553.2 (M+H)⁺, t_(R)=5.2 min (method 3).

Example 523-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-2,2-dimethyl-propionicAcid

Step 52A:4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-[2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-N-methyl-benzamide

4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide(200 mg, 0.46 mmol) was dissolved in DMF (2 mL) and3-bromo-2,2-dimethyl-propan-1-ol (72 μL, 0.94 mmol) and K₂CO₃ (192 μL,1.08 mmol) were added. The mixture was stirred at 65° C. for 24 hrs,cooled to rt, diluted with EtOAc, washed with water and brine, dried(Na₂SO₄), filtered and concentrated. Silica gel column chromatography(1% MeOH in DCM with gradient up to 5% MeOH in DCM) followed by prepHPLC afforded4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-[2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-N-methyl-benzamide.MS: 518.3 (M+H)⁺, t_(R)=6.16 min (method 3).

Step 52B.3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-2,2-dimethyl-propionicAcid

To periodic acid (68 mg, 0.30 mmol) in CH₃CN (200 μL) at 0° C.,Cr(VI)oxide (0.7 mg, 0.0073 mmol) was added and the mixture was stirredfor 15 min at 0° C. A solution of4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-[2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-N-methyl-benzamide(29 mg, 0.056 mmol) dissolved in CH₃CN (200 μL) was added and themixture was warmed to rt. After 2 hr at rt, the mixture was filtered,rinsed with CH₃CN, concentrated, dissolved in MeOH and purified by prepHPLC yielding3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-2,2-dimethyl-propionicacid 52-1. MS: 532.3 (M+H)⁺, t_(R)=3.65 min (method 3).

Example 53N-{2-[2-(2-Amino-ethylcarbamoyl)-ethoxy]-phenyl}-4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methylbenzamide

Step 52A:N-{2-[2-(2-Amino-ethylcarbamoyl)-ethoxy]-phenyl}-4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methylbenzamide

To a mixture of3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicacid 11-4 (50 mg, 0.10 mmol) and (2-amino-ethyl)-carbamic acidtert-butyl ester (51.5 mg, 0.54 mmol) in DMF (500 μL), EDCl (22 mg, 0.12mmol), HOBt (16 mg, 0.12 mmol) and DIPEA (34 μl, 0.19 mmol) were added.The mixture was stirred for 48 hrs at rt, diluted with MeOH (500 ILL)and purified by prep HPLC to afford{2-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionylamino]-ethyl}-carbamicacid tert-butyl ester. After treatment with 50% TFA in DCM (1 mL) for 2hrs, followed by concentration in vacuo,N-{2-[2-(2-amino-ethylcarbamoyl)-ethoxy]-phenyl}-4-chloro-3-(4-cyano-trifluoromethyl-pyridin-3-yl)-N-methyl-benzamide53-1 was obtained. MS [M+H]⁺ 546.1; t_(R)=5.66 min (method 2).

Similarly4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-[2-(3-oxo-3-piperazin-1-yl-propoxy)-phenyl]-benzamide53-2 was prepared. MS [M+H]⁺ 572.1; t_(R)=5.89 min (method 2).

It will be appreciated that, although specific embodiments of theinvention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptas by the appended claims.

We claim:
 1. The compound that is3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionicacid, or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier ordiluent.
 3. The compound that is4-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-butyricacid, or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising the compound of claim 3, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier ordiluent.